EU-Funded FP6 Research Projects on Antimicrobial Drug Resistance

EU-funded FP6 Research projects on Antimicrobial Drug Resistance

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EU-funded FP6 Research projects on Antimicrobial Drug Resistance

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ISBN 978-92-79-16745-4 doi:10.2777/22731

Introduction 6

ABS INTERNATIONAL COMBIG-TOP Implementing antibiotic strategies (ABS) Combinatorial biosynthesis of industrial for appropriate use of antibiotics in hospitals glycopeptides: technology, optimization in member states of the European Union 8 and production 27

ACE Approaches to control multi-resistant CombiGyrase enterococci: studies on molecular ecology, Development of new gyrase inhibitors horizontal gene transfer, fitness and prevention 10 by combinatorial biosynthesis 29

ACE-ART Assessment and critical evaluation of antibiotic resistance transferability CRAB in food chain - ACE-ART 12 Combating resistance to antibiotics 31

ActinoGEN Integrating genomics-based applications DRESP2 to exploit actinomycetes as a resource Role of mobile genetic elements in the spread for new antibiotics 14 of antimicrobial drug resistance 32

e-Bug Development and dissemination AMIS of a school antibiotic and hygiene Antimicrobials by immune stimulation 16 education pack and website across Europe 33

EACCAD ANTIBIOTARGET European approach to combat outbreaks Molecular and functional genomic approaches of Clostridium difficile associated diarrhoea to novel antibacterial target discovery 17 by development of new diagnostic tests 35

BACELL HEALTH EAR Bacterial stress management relevant Effects of antibiotic resistance on bacterial to infectious disease and biopharmaceuticals 19 fitness, virulence and transmission 36

BURDEN EARSS Burden of resistance and disease The European antimicrobial resistance in European nations 21 surveillance system 37

CanTrain Host-pathogen interaction systems as tools ERAPharm to identify antifungal targets in C. albicans Environmental risk assessment and C. dubliniensis 22 of pharmaceuticals 39

CHAMP Changing behaviour of healthcare professionals ESAC and the general public towards a more prudent European surveillance use of anti-microbial agents 24 of antimicrobial consumption 41 COBRA Combating resistance to antibiotics by broadening the knowledge on molecular ESSTI mechanisms behind resistance to inhibitors European surveillance of sexually transmitted of cell wall synthesis. 25 infections 43 GRACE ET-PA Genomics to combat resistance Enabling techniques for the development against antibiotics in community-acquired LRTI of a novel class of protein antibiotics 45 in Europe 67

HAPPY AUDIT EU-IBIS Health alliance for prudent prescribing, yield Invasive bacterial infections surveillance and use of antimicrobial drugs in the treatment in European Union 46 of respiratory tract infections 69

EUCAST European committee IPSE on antimicrobial susceptibility testing 49 Improving patient safety in Europe 71 LeishEpiNetSA Control strategies for visceral leishmaniasis (VL) EUR-INTAFAR and mucocutaneous leishmaniasis (MCL) Inhibition of new targets in South America: for fighting antibiotic resistance 51 applications of molecular epidemiology 73 EURESFUN Integrated post-genomic approaches MagRSA for the understanding, detection Fully automated and integrated microfluidic and prevention of antifungal drug platform for real-time molecular diagnosis resistance in fungal pathogens 53 of methicillin-resistant Staphylococcus aureus 75

EuResist Integration of viral genomics MalariaPorin with clinical data to predict response Validation of the plasmodium aquaglyceroporin to anti-HIV treatment 55 as a drug target 76 Eurofungbase Strategy to build up and maintain an integrated sustainable European fungal genomic database required MANASP for innovative genomics research on filamentous Development of novel management strategies fungi important for biotechnology and human health 57 for invasive aspergillosis 77

EPG micro-MATRIX European virtual institute for functional Workshop on strategies to address genomics of bacterial pathogens – antimicrobial resistance through EuroPathoGenomics 59 the exploitation of microbial genomics 78

EuropeHIVResistance MOSAR European cohort coordinating network Mastering hospital antimicrobial resistance and on HIV drug resistance 60 its spread into the community 79

EuroTB NewHiv Targets Surveillance of tuberculosis in Europe 62 Identifying novel classes of HIV inhibitors 81 NEWTBDRUGS New drugs for persistent tuberculosis: FUNGWALL exploitation of 3D structure The fungal cell wall as a target of novel targets, lead optimisation for antifungal therapies 64 and functional in vivo evaluation 82

GENOSEPT NM4TB Genetics of sepsis in Europe 66 New medicines for tuberculosis 83 NPARI Tailoring of novel peptide coatings and therapeutics derived from a newly identified Tat machine component of the human innate immunity Functional genomic characterisation against resistant infections 85 of the bacterial Tat complex 103

Phagevet-P Veterinary phase therapies as alternatives TB Treatment Marker to antibiotics in poultry production 86 Establishing a TB treatment efficacy marker 105 TB-DRUG OLIGOCOLOR Development of a molecular platform PNEUMOPEP for the simultaneous detection New methods of treatment of Mycobacterium tuberculosis resistance of antibiotic-resistant pneumococcal disease 88 to rifampicin and fluoroquinolones 106

PREVIS TRAINAU Pneumococcal resistance epidemicity Training risk assessment in non-human and virulence – an international study 89 antimicrobial usage 107

READ-UP TRIoH Redox antimalarial drug discovery 91 Targeting replication and integration of HIV 109 Tuberculosis China REBAVAC The diversity of Mycobacterium tuberculosis Novel opportunities to develop vaccines strains in China: tracing the origins to control antibiotic resistant bacteria: of theworldwide dispersion of the multidrug- from the trials back to the laboratory 92 resistant Beijing genotype 111

REPLACE UNITE-MORE Plants and their extracts and other natural Uniformity in testing alternatives to antimicrobials in feeds 93 and monitoring HIV resistance 112 SAFEWASTES Evaluating physiological and environmental consequences of using organic wastes after VIRGIL technological processing in diets European vigilance network for the for livestock and humans 95 management of antiviral drug resistance 113

SavinMucoPath Novel therapeutic and prophylactic strategies to VIROLAB control mucosal infections A virtual lab for decision support by South American bacterial strains 96 in viral diseases treatment 116

SIGMAL Targeting malaria transmission through VITBIOMAL interference with signalling in Plasmodium Vitamin biosynthesis as a target falciparum gametocytogenesis 98 for antimalarial therapy 117

SLIC Biosensors in molecular diagnostics nanotechnology for the analysis of species- specific microbial transcripts 100 Index of Acronyms 118 StaphDynamics Functional genomic characterisation of molecular determinants for staphylococcal fitness, virulence and drug resistance 101 Index of Coordinators 119 6 |

Introduction

Combating antimicrobial drug resistance The discovery and use of antibiotics has had an enormous impact on our healthcare system. Nowadays, the treatment and prevention of microbial infections fully depends on the availability of effective antibiotics. In addition to this, advanced surgical procedures like organ transplants, cancer chemotherapy and care of preterm babies heavily rely on effective antibiotics. Unfortunately, the emergence of and rise in resistance to the currently available antimicrobial drugs threatens the treatment of both hospital- and community-acquired bacterial infections and endangers many modern medical practices. This situation is further aggravated by a sharp decline in the discovery of new antimicrobial drugs needed to overcome drug resistance. Such developments represent a looming crisis for our healthcare system.

It is crucial to contain antimicrobial drug resistance (AMDR) and to nourish research aimed at combating it. This research need has been addressed within the EU framework programmes where AMDR has been given a high priority over the last decade with significant financial support from the Health Directorate of the Directorate-General for Research (DG RTD) in the European Commission.

The development and spread of AMDR are amongst the areas that are currently being investigated together with novel evidence- based approaches to managing patients with a view to optimising antibiotic use. 7 |

In addition, the discovery and develop- will result from several projects that have ment of novel antimicrobial drugs and the received funding. Within such projects identification of their molecular targets are attention is also being paid to the trans- areas that have attracted funding. This is of fer of resistance as well as the biological prime importance since only few antimi- costs (fitness costs) of resistance. The crobial agents have been launched during third area concerns the development of the last 30 to 40 years. Under-investment novel antimicrobial drugs that will ben- in antibiotic research and development by efit from research projects that aim to the pharmaceutical industry has con- identify compounds capable of inhibiting tributed to this problem. The research processes that are essential for bacte- projects that are supported by the Health rial growth or projects explore natural Directorate of DG RTD aim to form and resources to obtain new antimicrobials. support multidisciplinary collaborations, obtain a critical mass of researchers Under FP6, the total EC contribution investigating AMDR within Europe and committed to discovery and transla- mobilise the European biotech industry. tional research activities for projects that specifically focus on AMDR or on cer- The project catalogue contains informa- tain aspects of AMDR is more than EUR tion about AMDR projects funded under 160 million. In addition, several closely the Sixth Framework Programme (FP6). related projects funded by the Directo- It provides an overview of the scientific rate-General for Health and Consumer challenges, the research goals addressed Protection (SANCO) are also included and the expected outcome of projects. for a comprehensive overview of the The information presented also shows the scope of Community funding in this field. involvement and participation of a multitude However, although vaccination may have of small and medium-sized enterprises a significant impact on reduced use of (SMEs) working in close collaboration with antibiotics, no vaccine research projects the academic institutions. The concerted have been included in this compilation. efforts of the research consortia will most likely result in significant advances in three Research projects in this catalogue are distinct areas. Firstly, a more appropri- of prime importance since this type of ate use of currently available antibiotics is research is essential for a continua- aimed at in order for these drugs to remain tion of the effective control of bacterial effective as long as possible. Secondly, an infections that is required to sustain our increase of our current knowledge of the current high level of medical care as well biological processes that underlie AMDR as public trust in our healthcare system. 8 | ABS INTERNATIONAL Implementing antibiotic strategies (ABS) for appropriate use of antibiotics in hospitals in member states of the European Union http://www.abs-international.eu

BACKGROUND AIMS The ABS INTERNATIONAL project sought The general objectives of the project were: to further develop organisational com- petencies regarding adequate antibiotic to develop organisational tools and use in the cooperating hospitals of the qualified capacities for identifying partner countries, as well the qualification and distributing best practice on the of doctors and pharmacists in adequate prudent use of antimicrobial agents antibiotic use. Through eight Work in human medicine in hospitals; Packages (WPs), the project developed to enhance and implement spe- and validated quality indicators and cific strategies for the prudent use of process measures for antibiotic use. antimicrobial agents in hospitals; to elaborate methods for evaluating Problem: the applied antimicrobial strategies; In human medicine, the use of antibacterial to disseminate project results. agents for the treatment of viral infections and the unjustified use of substances with an extremely broad activity spectrum are regarded as the main causes (among others) of the resistance problem.

EU Project: ABS International

1.1 1.4 1.5 1.6 1.7 1.8 Project Planning and Process Preparation Implementation Preparation Management Preparation Measures/ per Partner per Partner of the QI for Country Country postprojet AB USe phase

1.2 Dissemination of Results

1.3 Evaluation of the Project

 Project number: 2005208  EC contribution: €798 598  Duration: 24 months  Starting date: 1 September 2006 ABS INTERNATIONAL | 9

OBTAINED RESULTS Partners The main deliverables Allerberger Franz, Burgmann Heinz, Janata of the project include: Oskar, Lechner Arno, Krause Robert, Mittermayer Helmut, Watschinger Regina, Wechsler-Fördös Agnes, Wenisch Christoph standards for ABS Tools; ABS Group Vienna, Austria ABS training and ABS consulting for cooperating hospitals; Dr. Cizman Milan University Medical Center country reports on the results Ljubljana, Slovenia of the ABS maturity survey; ‘Guidelines to Further Develop and Dr. Cornaglia Giuseppe Define Antibiotic Use in Hospitals’; University of Verona Verona, Italy ABS expert network.

ABS INTERNATIONAL is further develop- Prof. Hryniewicz Waleria National Institute of Public Health ing the strategy for the prudent use of Warsaw, Poland antimicrobial agents in hospitals and for the distribution of best practice including Dr. Jindrak Vlastimil training among 9 countries of the European Na Homolce Hospital Prague, Czech Republic Union, 4 of which are new Member States.

Dr. Kern Winfried Project Coordinator University Hospital Freiburg Prof. Dr Roland Gareis Freiburg, Germany and Mag. Annegret Frank Roland Gareis Consulting Silbergasse 30 Dr. Mechtler Reli 1190 Vienna, Austria Johannes Kepler University Linz Tel. +43 13677022-0 Linz, Austria Fax +43 13677022-70 E-mail: [email protected] Prof. Struelens Marc Hôpital Erasme Bruxelles Brussels, Belgium

Prof. Ternak Gabor University of Pecs Pecs, Hungary

Prof. Vladimir Krcmery St Elizabeth University of Health Bratislava, Slovakia 10 | ACE Approaches to control multi-resistant enterococci: studies on molecular ecology, horizontal gene transfer, fitness and prevention http://www.aceproject.eu/project_outline.php

BACKGROUND a typing scheme for resistant plasmids Genetic population analyses of Enterococ- to construct a catalogue of resistance cus faecium revealed the presence of a determinants, transposons, and plas- High-Risk Enterococcal Clonal Complex mids present in different host groups. (HiRECC) resistant to multiple antibiotics and responsible for most nosocomial VRE Potential applications: (vancomycin-resistant E. faecium and En- ACE is expected to contribute to new terococcus faecalis) infections and hospital strategies that will reduce the spread of outbreaks worldwide. In ACE, the evolution- resistance and infections, and create an ary development of HiRECC in E. faecium opportunity to develop vaccination which and E. faecalis will be further unraveled and could prevent infection and colonisation, combined with new knowledge on intra- respectively, with multi-resistant HiRECC. and inter-species gene transfer, and biological fitness costs of hospital adaptation. Project Co-Coordinators Prof. Marc J. M. Bonten Problem: and Dr Rob J. L. Willems Eijkman-Winkler laboratory for Microbiology, Nosocomial VRE infections are rising in Infectious Diseases and Inflammation Europe, with proportions of more than Heidelberglaan 100, Room G04.614 3584 CX Utrecht, Netherlands 10% among enterococcal bloodstream Tel. +31 2507394; +31 2507630 infections in 9 countries in 2005 (Fig. 1). Fax +31 2541770 Email: [email protected]; AIMS [email protected] The main project objectives include: Partners Dr Anette Marie Hammerum National Center for Antimicrobials and Infection determining the population structure Control of enterococci and the evolution- Copenhagen, Denmark ary development of HiRECC; Dr Lars Jensen improving understanding of the Technical University of Denmark biological fitness costs of hospi- Copenhagen, Denmark tal adaptation of Enterococci. Prof. Arnfinn Sundsfjord Universitetet I Tromsoe EXPECTED RESULTS Tromso, Norway The results ACE expects include: Prof. Ingolf Nes Universitetet for Miljo og Biovitenskap Ås, Norway improved MLST (multi-locus sequence typing) scheme for E. faecium and E. faecalis leading to the identification of HiRECC, community and animal associated clonal complexes.

 Project number: LSHE-CT-2007-037410  EC contribution: €3 148 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 February 2007 ACE | 11

Dr Johannes Huebner Prof. Waleria Hryniewicz Universitätsklinikum Freiburg für die Medizinische National Medicines Institute Fakultät der Albert-Ludwigs-Universität Warsaw, Poland Freiburg, Germany Marco van Es Winclove Bio Industries BV Dr Guido Werner Amsterdam, Netherlands Robert Koch Institute Wernigerode, Germany Dr Herman Groen IQ Corporation BV Prof. Fernando Baquero Groningen, Netherlands Fundacion para la Investigacion Biomedica Dr Kees Leenhouts Hospital Universitario Ramon y Cajal Stichting Biomade Technology Madrid, Spain Groningen, Netherlands

Israel 46.5 Cyprus 40 Greece 37.4 Portugal 33.7 Ireland 31.4 Bulgaria 14.3 Belgium 14 Czech Republic 13.7 Germany 11.3 Croatia 5.9 Spain 4.8 Austria 0.2 Sweden 0.8 Slovakia Romania Norway The Neterlands Malta Iceland Hungary Finland Estonia

Figure 1. Proportion vancomycin non-susceptible enterococcal blood isolates, EARSS 2005 (www.earss.rivm.nl). 12 | ACE-ART Assessment and critical evaluation of antibiotic resistance transferability in food chain - ACE-ART

http://www.aceart.net

BACKGROUND AIMS The ACE-ART project aimed to provide ACE-ART aimed to provide a critical evalu- a critical evaluation of the impact on ation of the role of antibiotic use in agricul- non-pathogenic bacteria of antibiotic ture, and in the prophylaxis and treatment use in agriculture, and in the prophylaxis of disease in humans. Unlike other studies, and treatment of disease in humans. The focused on pathogens, this project is fo- consortium established collaboration with cused on non-pathogenic bacteria. Strains the Joint Action Team of the International belonging to Lactobacillus, Bifidobacte- Organization for Standardization (ISO) and rium, Lactococcus and Streptococcus the International Dairy Federation (FIL/IDF). thermophilus have been used as they can be found in a wide range of habitats. A total of four Work Packages (WPs) fo- Moreover, they are industrially important cused on the development of standardised bacteria, used as starter cultures for phenotypic procedures, the validation of fermented food. Within this project the im- model systems for gene transfer evalu- portance of these bacteria as a source of ation, the genetic basis of the detected antibiotic resistance genes (Work package resistances and transmission mechanisms, 1) will be assessed. The project will also and the dissemination of project results. examine the transmission of resistance in the environment and in the animal and hu- Problem: man gut (WP 2) and establish the genetic The emergence and evolution of antibiotic basis of the detected resistances and resistance in bacteria represents a major transmission mechanisms (WP 3). Dissem- financial and societal cost. Despite concern ination of results and links with consumers’ that the use of antibiotics in the food chain organization will be provided by WP4; an contributes to the development of resist- industrial platform will assure the link with ant bacteria, research has yet to provide 14 industries producing starter cultures. the data necessary for the development This research will sought to establish a of an effective risk management strategy. dataset on the occurrence and transmis- Risk assessment of antibiotic resistant, sion of antibiotic resistance, providing the non pathogenic bacteria present in the scientific basis for an antibiotic application food chain requires data on the sources strategy to inhibit the further development of these bacteria, their genetic composi- of resistance in pathogenic bacteria. tion and potential for resistance transfer. The assessment of drug resistance is a mandatory requirement in the approval process of EFSA for bacterial feed additives and plant protecting agents.

 Project number: CT-2003- 506214  EC contribution: €2 462 000  Duration: 36 months (+6 of extension)  Type: Specific Targeted Research Project  Starting date: 1 January 2004 ACE-ART | 13

OBTAINED RESULTS Partners A phenotypic procedure to evaluate the Dr Andrea Wilcks drug resistance profile of food bacteria Danish Institute for Food and Veterinary Research Søborg, Denmark was developed; this procedure is now the ISO method. New MIC were provided Dr Eric Johansen Chr. Hansen A/S to the European Food Safety Author- Hørsholm, Denmark ity (EFSA) for safety evaluation of these Dr Abelardo Margolles bacteria; data provided by ACE-ART has Instituto de Productos Lácteos de Asturias (IPLA) been used to update the guidelines for Villaviciosa, Asturias, Spain bacterial safety evaluation. This achieve- Dr Maria Saarela ment is significant, as this support to VTT Biotechnology (VTT Technical Research Centre of Finland) EU policy was a project objective. Espoo, Finland Prof. Karen A. Krogfelt Potential applications: Statens Serum Institut Methodology developed by ACE- Copenhagen, Denmark ART and MIC can be used by the in- Dr Lars Axelsson dustry in the process for developing Norwegian Food Research Institute Osloveien, Norway new starter or probiotic bacteria. Prof. Jacek Bardowski Instytut Biochemii i Biofizyki PAN Project Coordinator Warsaw, Poland Prof. Lorenzo Morelli Istituto di Microbiologia Dr Declan Bolton Università Cattolica Sacro Cuore TEAGASC – The National Food Centre Via Emilia Parmense 84 Dublin 15, Ireland 29100 Piacenza, Italy Dr Henricus Jozef Maria Aarts Tel: +39 0523599248 RIKILT Institute of Food Safety – MCB Fax: +39 0523599246 Wageningen, Netherlands E-mail: [email protected] Prof. Atte Johannes von Wright University of Kuopio Kuopio, Finland Dr Wolfgang Kneifel Univerisity of Natural Resources and Applied Life Sciences Vienna, Austria Prof. Jean Swings Ghent University Ghent, Belgium Dr Sven E. Lindgren Swedish National Food Administration Uppsala, Sweden 14 | ActinoGEN Integrating genomics-based applications to exploit actinomycetes as a resource for new antibiotics

http://www.swan.ac.uk/research/ActinoGEN/

BACKGROUND three parallel objectives to discover and ActinoGEN is an Integrated Project aimed develop new antibiotics based on exploiting at developing novel genomics-based ap- the genetic resources of actinomycetes: proaches to exploit hitherto overlooked genetic resources for new antibiotics. To 1. activate cryptic antibiotic greatly accelerate the drug discovery proc- biosynthetic pathways; ess, a parallel strategy will be to engineer 2. rely on the discovery of new generic hosts optimised to produce high antibiotic biosynthetic pathways antibiotic yields. With the complete genome from diverse actinomycetes; sequence of the model actinomycete, 3. follow through on combining Streptomyces coelicolor, and mobilisation biosynthetic pathways to direct of a pan-European effort to apply newly synthesis of new antimicrobials. developed multidisciplinary post-genomic technologies, a holistic understand- EXPECTED RESULTS ing of the physiology and regulation of ActinoGEN expects to achieve the antibiotic biosynthesis is achievable for following results, among others: the first time. This will, in turn, permit rational intervention to engineer generic 1. establishment of generic procedures hosts for high-yield antibiotic produc- for the activation of cryptic tion. This synergy of discovery linked to antibiotic biosynthetic pathways; overproduction will place the European 2. expression of a variety of biotechnology sector at the forefront of heterologous cryptic pathways after developing much-needed new antibiotics their transfer to defined superhost to combat multi-drug resistant pathogens. antibiotic production strains; 3. establishment of refined genomic- Problem: based procedures for analysis Multiple drug-resistant bacteria are a of metagenomes to identify new major threat to human health and a antibiotic biosynthetic pathways; significant burden on already stretched 4. optimised expression of new medical budgets. This threat is predicted to combinatorial antibiotics, increase in severity. Of major concern are together with structural analysis antibiotic-resistant nosocomial infections. and antimicrobial spectra; 5. generic antibiotic production superhosts AIMS derived by rational genomics-driven The aim of ActinoGEN is to combine new manipulation of S. coelicolor; functional genomic technologies with 6. refined superhost strains optimised for chemical analysis in an integrated multidis- production of key new antimicrobials. ciplinary approach. ActinoGEN proposes

 Project number: LSHM-CT-2004-005224 EC contribution: €9 384 133  Duration: 60 months  Type: Integrated Project  Starting date: 1 January 2005 ActinoGEN | 15

Potential applications: Dr Greg Challis The development of new technologies for University of Warwick Coventry, England, UK antibiotic discovery and production will benefit European small and medium-sized Prof. Wolfgang Wohlleben, Dr Jens Reuther, Prof. Lutz Heide enterprises (SMEs) in the biotechnology Eberhard Karls-Universität Tübingen sector. Application of these new genomics- Tübingen, Germany based procedures and technologies for Prof. Colin Smith discovery and exploitation of natural prod- University of Surrey Guildford, England, UK ucts can provide a platform for a renais- sance in drug discovery after 15 years of Prof. Anna Maria Puglia Universita di Palermo stagnation. New antimicrobials discovered Palermo, Italy in the course of the project can potentially Prof. Lubbert Dijkhuizen and Dr Eriko Takano help alleviate the current crisis in treatment Groningen Biomolecular Science and of multiple drug-resistant pathogens. Biotechnology Institute, Rijksuniversiteit Groningen, Netherlands Project Coordinator Dr Marie-Joelle Virolle and Prof. Jean-Luc Pernodet Prof. Paul Dyson Université Paris-Sud Swansea University Orsay, France School of Medicine Institute of Life Science Dr Roderich Süssmuth Singleton Park Technische Universität Berlin Swansea, SA2 8PP, Wales, UK Berlin, Germany

Tel. +44 1792295667 Dr Francisco Moris Fax +44 1792602280 EntreChem SL E-mail: [email protected] Mieres, Spain Partners Prof. José Salas Universidad de Oviedo Prof. Mervyn Bibb Oviedo, Spain John Innes Centre Norwich, England, UK Prof. Juan Francisco Martin Dr Jiri Vohradsky Institute of Biotechnology of León Academy of Sciences of the Czech Republic León, Spain Prague, Czech Republic Prof. Pierre Leblond and Dr Bertrand Aigle Prof. Douglas Kell Institut National University of Manchester Institute de la Recherche Agronomique (INRA) of Science and Technology Vandoeuvre les Nancy, France Manchester, England, UK Dr Renaud Nalin Dr Anna Eliasson Lantz Libragen Technical University of Denmark Villeurbanne, France Kgs. Lyngby, Denmark Prof. Kye Joon Lee Seoul National University Seoul, South Korea 16 | AMIS

Antimicrobials by immune stimulation

BACKGROUND Potential applications: AMIS sought to use the strength of the innate The collaborative research will lead immune system to design antimicrobial drugs to proof-of-principle for a novel treat- for future generations. Antimicrobial proteins ment approach to address antimicro- are often combined with inflammatory signals bial resistance by combining the innate in one single molecule. AMIS took that same immuno-stimulation with the antimicrobial approach and reshuffled different parts of capacity of naturally occurring substances different molecules to make novel effector of the human innate immune system. molecules that still have these combined functions but are optimally adapted for Project Coordinator therapeutic intervention. The consortium selected the most promising and innovative Dr Jos van Strijp University Medical Centre Utrecht compounds with this dual mode of action. Eijkman Winkler Institute Heidelberglaan 100 3584 CX Utrecht, Netherlands Problem: Tel. +31 302506528 The success with which antibiotics have Fax +31 302541770 been used to combat infectious dis- E-mail: [email protected] eases is under serious threat from the Partners increasing development of antimicrobial Prof. Martin Krönke resistance. To fight infectious diseases University of Cologne effectively, we have to broaden the ap- Cologne, Germany proaches in therapeutic intervention. Prof. Terje Espervik Norwegian University of Science and Technology Trondheim, Norway AIMS Activators, receptors, effectors and in- Prof. Andreas Peschel University Hospital Tübingen hibitors are an integral part of the complex Tübingen, Germany mechanism of interaction in the innate im- Prof. Lars Björck mune system, combining cellular stimulation Lund University and anti-microbial action. These interaction Lund, Sweden mechanisms formed the core focus of AMIS. Dr Henk P. Haagsman Utrecht University EXPECTED RESULTS Utrecht, Netherlands The partners expect to make an array Dr Peter Antal-Szalmas of fusion proteins that combine strong University of Debrecen Debrecen, Hungary antimicrobial with inflammatory signals so that these two actions work in concert. Dr Herman Groen IQ Corp Furthermore, the consortiumwill investi- Groningen, Netherlands gate how theinnate immune system can Dr Shai Yarkoni effectively recognise and kill a bacterium Target-In Ltd without developing major resistance. Kfar Saba, Israel

 Project number: LSHM-CT-2004-512093  EC contribution: €2 100 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2005 ANTIBIOTARGET | 17 Molecular and functional genomic approaches to novel antibacterial target discovery http://antibiotarget.nottingham.ac.uk/

BACKGROUND with novel modes of action is a major The ANTIBIOTARGET project will estab- threat to public health worldwide. lish an innovative research-driven training programme in state-of-the-art technolo- AIMS gies in the fields of molecular bacterial The research project will focus on Pseu- pathogenicity, functional genomics and domonas aeruginosa as a model pathogen biological chemistry directed towards since it is an important, intrinsically resist- the development of novel antibacterial ant Gram negative bacterium responsible therapies which combat the disease- for high infection rates in humans within causing and natural antibiotic resist- the hospital environment, has a completely ance capacity of pathogenic bacteria. sequenced genome, is highly amenable to genetic manipulation and the ANTI- Problem: BIOTARGET partners are all recognized Infectious diseases account for more international research leaders in the than 13 million deaths a year (one in two molecular biology, biochemistry, genet- deaths in developing countries) and are ics and pathogenicity of Pseudomonas. In the main causes of mortality and morbid- addition, the ubiquitiness of this organism ity around the world. Increasing human would make any new discoveries potentially mobility and changing social patterns as applicable to other nosocomial pathogens. well as the increasing number of immuno- Given the major threat to human health compromised individuals as a result of posed by multi-antibiotic resistance, the ageing populations, AIDs and advances in strategies used in this project will offer not surgery and cancer chemotherapy, have only a timely opportunity to discover new all increased the spread and risk of infec- antibacterial targets but also to provide tion. Furthermore, the WHO has stated a pool of highly skilled scientists with that “no population is more vulnerable to specific expertise directed towards the multi-drug resistance than those admit- discovery of novel anti-infective agents. ted to hospital wards”. Consequently, the spread of antibiotic resistant bacteria in ANTIBIOTARGET will identify targets hospitals means that medical procedures involved in promoting or regulating at- once previously taken for granted may tachment, the biofilm lifestyle, virulence, have to be abandoned with enormous and intrinsic antibiotic resistance, and will impacts on morbidity and mortality. develop strategies for discovering new agents that inhibit the ability of bacte- The emergence of multi-antibiotic resistant ria to colonise tissues, cause disease bacteria and the failure of drug discovery and resist conventional antibiotics. programmes over the last 10 years to provide new broad-spectrum antibiotics

 Project number: MEST-CT-2005-020278  EC contribution: €2 171 791  Duration: 48 months  Type: Marie Curie Actions-Early-Stage Training  Starting date: 1 March 2006 18 | ANTIBIOTARGET

EXPECTED RESULTS Project Coordinator Using the Pseudomonas aeruginosa as a Prof. Miguel Cámara model pathogen, ANTIBIOTARGET will: Institute of Infection, Immunity and Inflammation School of Molecular Medical Sciences Centre for Biomolecular Sciences identify key genes contribut- University of Nottingham Nottingham, England, UK ing to attachment, biofilm forma- Tel. +44 115951 036 tion, intrinsic resistance, virulence Fax +44 1158467951 and damage to the host; E-mail: [email protected] engineer biosensor systems for Partners the screening of novel agents that Dr Romé Voulhoux will inhibit the infection process; IBSM-CNRS Marseille, France identify natural products, enzymes and small compounds inhibiting attach- Prof. Wim Quax University of Groningen ment, virulence, biofilm development Groningen, Netherlands and promoting antibiotic susceptibility; Prof. Karl Jaeger develop large-scale production of Heinrich-Heine-Universität Düsseldorf pharmaceutical products identified Forschungszentrum Jülich Jülich, Germany in this project for industrial use. Prof. Alain Filloux Imperial College London Potential applications: London, England, UK ANTIBIOTARGET will help the scientific community to better understand the molecular mechanisms used by P. aeruginosa to cause disease, and the results will be directly applicable to other bacteria of relevance to public health. The project will also generate a number of new biosensor systems in Pseudomonas which will be ex- ploited for the screening of novel inhibitors of virulence factor production, as well as develop ‘designer’ organisms to increase the production of proteins and chemical compounds that can be used therapeutically to treat Pseudomonas infections. BACELL HEALTH | 19 Bacterial stress management relevant to infectious disease and biopharmaceuticals http://www.bacell.eu/health

BACKGROUND AIMS The BACELL HEALTH project was de- The primary objective was to develop a signed to gain new knowledge in the field detailed understanding of the integra- of bacterial cell biology for the develop- tive Cell Stress Management System and ment of new products and processes. The associated stress resistance processes project aimed to address both the harmful that are essential for sustaining bacteria as and beneficial characteristics of bacterial effective pathogens or producers of phar- behaviour by undertaking an integrated maceutically active proteins and peptides. and in-depth study of the response of Gram-positive bacteria to stress. EXPECTED AND OBTAINED RESULTS The consortium created four experimental The project will develop an understanding Work Packages (WPs), each with specific of the regulatory networks underlying the milestones and deliverables: WP1 focused response of environmental bacteria and on a detailed understanding of how B. sub- pathogens to stresses encountered during tilis regulates its metabolism in response infection and commercial bioprocesses. to environmental stresses; WP2 aimed to unravel the regulatory and biochemical Potential applications: processes that pathogens related to B. Potential new targets for antimicrobial subtilis need to ‘top up’ these responses; drugs, improved production of bioac- WP3 aimed at improving the ability of tive proteins and peptides, improved commercial strains of B. subtilis and its commercial production strains. close relatives to produce biopharmaceuticals; and WP4 focused on comparative genomics and network modelling.

Problem: The major challenge for the BACELL HEALTH consortium was to understand how individual regulatory pathways are networked to maintain cellular home- ostasis, using state-of-the-art post- genomic technologies; this is known as the Cell Stress Management System.

 Project number: LSHC-CT-2004-503468  EC contribution: €2 000 000  Duration: 48 months  Type: Specific Targeted Research Project  Starting date: 1 March 2004 20 | BACELL HEALTH

Project Coordinator Prof. Colin Harwood Cell and Molecular Biosciences Newcastle University Framlington Place Newcastle upon Tyne, England, UK Tel. +44 1912227708 Fax +44 1912227736 E-mail: [email protected]

Partners Prof. Kevin Devine Smurfit Institute Trinity College Dublin Dublin, Ireland Prof. Mohamed Marahiel Philipps Universität Marburg Marburg, Germany Prof. Wolfgang Schumann Bayreuth University Bayreuth, Germany Dr Tarek Msadek Institut Pasteur Paris, France Prof. Michael Hecker Universität Greifswald Greifswald, Germany Dr Marc Kolkman Danisco/Genencor Leiden, Netherlands Dr M.D. Rasmussen Novozymes A/S Bagsværd, Denmark Dr Rocky Cranenburgh Cobra Biomanufacturing Keele, England, UK Prof. Jan Marteen van Dijl and Prof. Oscar Kuipers Groningen University Groningen, Netherlands BURDEN | 21

Burden of resistance and disease in European nations http://www.eu-burden.info

BACKGROUND identification, on a country-by-country The emergence and spread of antimicrobial basis, of information needs of different resistance (AMR) has become a major public stakeholders for their own assessment health threat, and infections caused by of the burden of infectious diseases antimicrobial resistant pathogens continue to caused by antimicrobial susceptible increase in the EU and abroad. These infec- and resistant bacterial pathogens; tions cause suffering, incapacity and death, identification of incentives and coun- and impose an enormous financial burden terincentives that impinge on efforts on both healthcare systems and on society to control the spread of AMR; in general. The aim of the BURDEN project is demonstration of the human and soci- to provide realistic estimates of the burden of etal dimensions of infections caused by disease and the costs to societies attribut- resistant pathogens and the repercus- able to infections caused by antimicrobial sions for the healthcare systems. resistant pathogens in member states and accession countries of the European Union. Potential application: Politicians, policymakers and public health Problem: experts will be provided with valid data in There is a lack of data on the treatment out- order to prioritise and plan future health comes in infections due to antibiotic resistant political goals, as against other specific pathogens, in terms of attributable mortality, causes of morbidity and mortality in Europe. prolongation of hospital care and, above all, on the economic consequences for individu- Project Coordinator als and healthcare systems and societies. Prof. Dr Uwe Frank University Hospital Freiburg Institute of Environmental Medicine AIMS and Hospital Epidemiology The main specific objectives of BURDEN are: Freiburg, Germany Tel. +49 761 270 8210 E-mail: [email protected] to generate country-specific cost models for quantifying the eco- Partners: nomic loss due to AMR; Prof. Peter Davey University of Dundee to determine the excess mortal- Dundee, Scotland, UK ity, morbidity, length of stay and Dr Carl Suetens costs attributable to AMR; Institute of Public Health Brussels, Belgium to illustrate the financial impact of Prof. Hajo Grundmann AMR on care in European hospitals. National Institute of Public Health and the Environment EXPECTED RESULTS Bilthoven, Netherlands Prof. Dr Martin Schumacher The results the BURDEN partners Universitätsklinikum Freiburg expect include: Freiburg, Germany

 Project number: 2005203  EC contribution: €1 139 412  Duration: 36 months  Starting date: 1 July 2007 22 | CanTrain Host-pathogen interaction systems as tools to identify antifungal targets in C. albicans and C. dubliniensis

http://www.cantrain.be

BACKGROUND which are important for the expression The CanTrain network trained both early of virulent traits. To perform compara- and experienced researchers in the meth- tive genomics of C. albicans and C. odologies necessary for drug development, dubliniensis to identify genes absent including target identification and develop- in the less virulent C. dubliniensis. ment of cell-based screening assays. Objective 2 - To study the virulence of wild type and respective isogenic CanTrain addressed infectious diseases mutant C. albicans and C. dub- caused by fungal pathogens, and at- liniensis strains using human recon- tempted to establish approaches lead- stituted tissue systems and mouse ing to novel anti-fungal compounds by macrophages as model systems. combining the expertise of 11 partners Objective 3 - To study the mo- in cellular sensor systems and signal- lecular basis of host-pathogen ling pathways controlling morphogenesis interaction and virulence using and virulence, model systems for host- transcriptional profiling, proteom- pathogen interaction, assay develop- ics and biochemical approaches. ment and drug screening technologies. Objective 4 - To develop new cell-based assays for identifying AIMS potential novel antifungal substances The main objective of this network is to train in the context of host-pathogen both early and experienced researchers in interaction, including assay valida- the methodologies of drug development tion with clinical C. albicans and starting from target identification, target C. dubliniensis isolates and known validation, development of screening assays antifungal drugs and screening using and drug screening up to the identifica- combinatorial compound libraries. tion of lead compounds. CanTrain aimed to develop new screens and cell-based EXPECTED assays for identifying novel antifungal sub- AND OBTAINED RESULTS stances. The training gained was transfer- The partners bridged the gap between able to all fields involving drug screening. environmental stimuli inducing infection mechanism and the signal transduction The major research objec- pathways triggered by these stimuli. They tives can be outlined as follows: also characterised a G protein-coupled receptor that is important for the yeast- Objective 1 - To identify and charac- to-hyphae transition on solid medium, terize C. albicans and C. dubliniensis and identified several potential new membrane transporters and sensors targets for antifungal drug discovery in as well as downstream components both C. albicans and C. dubliniensis.

 Project number: MRTN-CT-2004-512481  EC contribution: €2 689 991  Duration: 48 months  Type: Marie-Curie Research Training Network  Starting date: 1 March 2005 CanTrain | 23

A number of training courses were Dr Derek Sullivan organised, including an in vitro bio- Dublin Dental School & Hospital, Trinity College Dublin 2, Ireland film course and a bioinformatics and microarray analysis course. Prof. Hana Sychrova The Academy of Sciences of the Czech Republic Prague 4, Czech Republic Project Coordinator Prof. Helena Bujdakova Prof. Patrick Van Dijck Comenius University Department of Molecular Microbiology, VIB Bratislava, Slovakia Laboratory of Molecular Cell Biology, K.U. Leuven Insitute for Botany and Microbiology Dr Renate Spohn Kasteelpark Arenberg 31 EMC microcollections GmbH 3001 Leuven, Belgium Tübingen, Germany Tel. +32 16321512 Fax +32 16321979 E-mail: [email protected]

Partners Dr Steffen Rupp Fraunhofer IGB Stuttgart, Germany Prof. Per Ljungdahl Stockholm University Stockholm, Sweden Dr Rosalia Diez-Orejas Universidad Complutense de Madrid Madrid, Spain Prof. Lubomira Stateva University of Manchester Manchester, England, UK Prof. Karl Kuchler Medical University Vienna Vienna, Austria Prof. Laura Popolo Università di Milano Milan, Italy 24 | CHAMP Changing behaviour of healthcare professionals and the general public towards a more prudent use of anti-microbial agents

BACKGROUND this field and to serve as a basis for CHAMP aims to promote the appropri- national and regional strategies. ate use of antibiotics by developing effective tools to change the behaviour Project Coordinator of healthcare professionals, patients in Prof. Th.J.M. Verheij primary care, and the general public on Julius Center for Health Sciences and Primary Care the prescription and use of antibiotics. University Medical Center Utrecht PO Box 85500 Problem: 3508 GA Utrecht, Netherlands Tel. +31 887568188 Antibiotics are priority drugs and bacterial Fax: +31 88 7568099 resistance is a major public health issue, and E-mail: [email protected] antibiotic consumption is a key driver of resist- Partners ance, although the relationships are complex. Prof. Herman Goossens Universiteit Antwerpen AIMS Antwerp, Belgium CHAMP aims to promote, through a series Prof. Paul Little of seven Work Packages, the appropriate University of Southampton use of antibiotics by developing effec- Southampton, England, UK tive tools to effect behavioural changes Prof. Christopher Butler of healthcare professionals, patients in Cardiff University Cardiff, Wales, UK primary care, and the general public on the prescription and use of antibiotics. Prof. Joanna Coast University of Birmingham Birmingham, England, UK EXPECTED Prof. Richard Smith AND OBTAINED RESULTS London School of Hygine & Tropical Medicine CHAMP will produce an inventory of attitudes London, England, UK

and expectations of both healthcare profes- Dr Maciek Godycki-Cwirko sionals and patients in primary care on antibi- Medical University of Lodz otic treatment in respiratory and urinary tract Lodz, Poland infections. It will also provide a state-of-the-art Dr Stephen Harbarth overview of behavioural interventions and Hôpitaux Universitaires de Genève public campaigns on antibiotic use and de- Geneva, Switzerland terminants of success and failure. Experts will Prof. Denise de Ridder formulate evidence-based advice to the Com- Utrecht University Utrecht, Netherlands mission on the preferred policy in order to improve antibiotic use in European primary care. Prof. Francesco Blasi Università degli Studi di Milano Milan, Italy Potential applications: Prof. Jesús Rodríguez-Marín The CHAMP final report can be used Universidad Miguel Hernández de Elche to formulate future European policy in Elche (Alicante), Spain

 Project number: SP5A-CT-2007-044317  EC contribution: €1 445 260  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 April 2007 COBRA | 25 Combating resistance to antibiotics by broadening the knowledge on molecular mechanisms behind resistance to inhibitors of cell wall synthesis.

BACKGROUND β-lactamases. This latter resistance can be COBRA targeted the elucidation of the enhanced by associated impermeability or molecular mechanisms of resistance to efflux mechanisms. Since many pathogens inhibitors of cell wall synthesis in bacteria are multiresistant, there will be an even- responsible for severe nosocomial and tual limitation in the choice of antibiotics community-acquired infections. Our STREP useful for primary treatment and therefore was focused on β-lactams, the major a promotion of a vicious cycle facilitat- class of antibiotics in current clinical use, ing the emergence of new resistances. and on resistance due to modifications of the cell wall synthesizing machinery and AIMS to production of β-lactamases, the most COBRA focused on the understand- prevalent mechanisms in Gram-positive ing of molecular mechanisms of re- and Gram-negative bacteria, respectively. sistance to β-lactams and other cell wall inhibitors in clinical Gram-positive Problem: and Gram-negative pathogens. Antibiotics are not like other drugs in that they act against bacteria and not the human EXPECTED host. Therefore the evolution of resistance AND OBTAINED RESULTS under the selective pressure of antibiotics The results anticipated by the CO- after exposure of populations (human, ani- BRA partners included: mal) raises major therapeutical issues. This program addresses the general problem of understanding the role of amino acid resistance to antibiotics and concerns the residues in PBPs that are essential for understanding of the mechanisms of resist- the expression of resistance and their ance, in particular to inhibitors of cell wall contribution to the structure of the synthesis. Among these are the β-lactams, PBP D, D-transpeptidase domains; one of the most important classes of understanding the genetic environ- antibiotics, if not the most broadly used ment of the β-lactamase genes and its antibiotics worldwide. The rates of β-lactam contribution to expression of resist- resistance for many common species found ance and gene dissemination. in infections have reached high levels in the community, as well as in the hospital. While Potential applications: In Gram-positive organisms this resistance The transmission and acquisition of resist- is mainly due to altered targets, in Gram- ance by new strains is one of the major negative organisms, acquired resistance to factors in resistance dissemination. Under- β-lactams is essentially due to the presence standing of the transmission mechanisms of plasmid-encoded β-lactamases or the is a crucial step in preventing resistance over-expression of chromosome-encoded and guiding optimal antibiotic usage.

 Project number: LSHM-CT-2003-5003335  EC contribution: €2 980 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 February 2004 26 | COBRA

Project Coordinator Prof. Rafaël Canton Prof. Laurent Gutmann Hospital Universitario Ramon y Cajal INSERM EMI0004/Université Paris VI Madrid, Spain Laboratoire de Recherche Moléculaire Dr David Martin Livermore sur les Antibiotiques Antibiotic Resistance Monitoring & Reference 15 rue de l’école de Médecine Laboratory 75270 Paris, France London, England, UK Tel. +33 1 42 34 68 62 Fax +33 1 423 25 68 12 Dr Marek Gniadkowski E-mail: [email protected]. National Institute of Public Health fr; [email protected]: Warsaw, Poland Partners Dr Timothy Rutland Walsh The University of Bristol Prof. Jean-Marie Frère Bristol, England, UK Centre d’Ingénierie des Protéines Liège, Belgium Prof. Gian Maria Rossolini Università degli Studi di Siena Dr Tanneke Den Blaauwen Siena, Italy Swammerdam Institute for Life Sciences Amsterdam, Netherlands Dr Jonathan Dando Inserm Transfert SA Prof. Regine Hakenbeck Paris, France University of Kaiserslautern Kaiserslautern, Germany Prof. Brigitte Berger-Bächi Institut für Medizinische Mikrobiologie/Universität Zürich Zuich, Switzerland Dr Juan Ayala Centro de Biología Molecular ‘Severo Ochoa’ Madrid, Spain Dr Dominique Mengin-Lecreulx Université Paris XI / IBBMC, UMR 8619 CNRS Orsay, France Prof. Timothy Bugg University of Warwick Coventry, England, UK Dr Thierry Vernet Institut de Biologie Structurale Grenoble, France Prof. Patrice Nordmann University Paris XI, UPRES 3539 Le Kremlin Bicêtre, France COMBIG-TOP | 27 Combinatorial biosynthesis of industrial glycopeptides: technology, optimization and production http://www.combigtop.uni-tuebingen.de

BACKGROUND OBTAINED RESULTS COMBIG-TOP focused on the genera- COMBIG-TOP generated novel peptide tion of new and more effective glycopep- backbones and elucidated the glycopeptide antibiotics by using combinatorial tide synthesis focusing on the synthesis of biosynthesis, and the faster development balhimycin by Amycolatopsis balhimycina. of new candidates by combining post- Genes involved in glycopeptide tailor- genomics techniques with modern ing reactions, such as glycosyl transfer, molecular biotechnology. High-quality were collected from different glycopeptide academic research tightly interconnected producers or identified by genetic screen- with industrial research and production ing. Novel glycopeptides with altered processes by two participating small and backbones, novel glycosylation patterns medium-sized enterprises (SMEs) was vital. and other structural modifications were developed. These drug candidates will be Problem: tested for their effectiveness as antibiotics. Due to the increasing frequency of Flux analyses and two-dimensional (2D) nosocomial infections caused by multi- maps were used to discover primary resistant bacterial pathogens, there is an metabolism proteins up-regulated dur- urgent need for novel and better antibi- ing glycopeptide production. Combined otics that can supplement the existing with a study of other limiting steps such armamentarium against pathogens. as precursor uptake, bottlenecks in the glycopeptide production could be AIMS identified and eliminated, allowing the COMBIG-TOP aimed to gener- construction of an improved production ate more effective glycopeptides by strain, also usable for the novel glyco- combinatorial biosynthesis and to peptides generated by the project. accelerate the development of promising glycopeptides through an im- Potential applications: proved fermentation process. New antibiotics for human health.

 Project number: LSH- 503491  EC contribution: €1 999 800  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2004 28 | COMBIG-TOP

Project Coordinator Prof. Dr Wolfgang Wohlleben University of Tübingen Institute of Microbiology Department of Microbiology/Biotechnology Auf der Morgenstelle 28 72076 Tübingen, Germany Tel. +49 070712976944 Fax +49 07071295679 E-mail: [email protected] tuebingen.de Partners Prof. Lubbert Dijkhuizen University of Groningen Haren, Netherlands Dr Jochen Förster Fluxome Sciences A/S Technical University of Denmark Kgs. Lyngby, Denmark Prof. Dr Mohammed Marahiel Philipps University of Marburg Marburg, Germany Prof. Jens Nielsen Technical University of Denmark Kgs. Lyngby, Denmark Dr Stefan Pelzer Combinature Biopharm AG Berlin, Germany Prof. Anna Maria Puglia University of Palermo Palermo, Italy Prof. John Robinson University of Zurich Zurich, Switzerland Prof. Dr Roderich Süßmuth Technische Universität Berlin Berlin, Germany CombiGyrase | 29

Development of new gyrase inhibitors by combinatorial biosynthesis

BACKGROUND Staphylococcus aureus (MRSA) infec- The bacterial enzyme DNA gyrase is tions, but vancomycin-resistant strains well validated as a target for a number of of S. aureus have already begun to antibacterial compounds. CombiGyrase emerge. Nowadays, the risk of infec- researched and developed new drugs tion increases with a prolonged hospital that are urgently needed. It represented stay, and so does failure of antibiotic an ideal platform to expand the diversity therapy because of multidrug resistance. of potent gyrase inhibitors found in nature by methods of combinatorial biosynthe- AIMS sis.Combinatorial biosynthesis is a novel CombiGyrase aimed to develop new anti- technology that uses genetic manipula- infectives targeting gyrase and/or bacterial tion to improve the chemical properties topoisomerase IV, evaluate the activity of and pharmacological activity of naturally these compounds as inhibitors of gyrase occurring compounds. Using microor- and of topoisomerase IV and of the result- ganisms which produce natural gyrase- ing antibacterial activity against bacterial inhibiting antibiotics, the CombiGyrase pathogens, and evaluate the suitability of consortium successfully demonstrated these compounds as drug candidates. that novel ‘designer’ antibiotics can be developed by combinatorial genetic The focus was on the development of methods. New gyrase-directed drugs, derivatives of the following antibiot- such as aminocoumarin and simocy- ics, which are produced by different clinone antibiotics, developed by these Streptomyces strains and represent methods, may help to overcome prob- highly potent inhibitors of gyrase: lems due to clinical resistance, and may significantly expand the clinical role of the the aminocoumarin antibiotics novo- gyrase inhibitors as antibacterial agent biocin, clorobiocin and coumermycin A1; the mixed aminocoumarin/angucy- Problem: cline antibiotic simocyclinone D8; A constant threat to the population of the mixed peptide/polyketide antibiot- the European Community is the ever- ics cyclothialidine and GR122222X. increasing problem of antibiotic resistance. Widespread use of antibiotics has led OBTAINED RESULTS to the emergence of antibiotic-resistant By using microorganisms that pro- strains. The increase and spread of duce natural gyrase-inhibiting antibi- resistance are a matter of serious public otics, the CombiGyrase consortium health concern worldwide. For example, successfully demonstrated that novel vancomycin has long been considered ‘designer’ antibiotics can be developed as the solution to methicillin-resistant by combinatorial genetic methods.

 Project number: 503466  EC contribution: €1 555 415  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2004 30 | CombiGyrase

CombiGyrase generated 33 new amino- Partners coumarins using genetically optimised Prof. Dr Lutz Heide microorganisms. The structures of these Universidad de Oviedo Oviedo, Spain compounds were elucidated, and the new antibiotics were tested for gyrase Prof. Andreas Bechthold Albert-Ludwigs-Universität Freiburg inhibition in vitro and in a cell-based Freiburg, Germany reporter gene expression assay, and for Prof. Anthony Maxwell their activity against bacterial pathogens. John Innes Centre A high-throughput assay for the ATPase Norwich, England, UK activity of gyrase B was established and Prof. Manlio Palumbo validated with known inhibitors. A sec- University of Padova Padua, Italy ondary assay for detecting the mode of action of novel anti-microbial compounds Dr Andreas Vente Combinature Biopharm AG was validated for gyrase B inhibitors. Berlin, Germany Prof. Malcolm Page The consortium discovered the mode Basilea Pharmaceutica Ltd of action of a completely novel class of Basel, Switzerland DNA gyrase inhibitors (simocyclinones). Simocyclinones share some structural similarities with aminocoumarins but also a number of differences. The partners found that these compounds target gyrase, and that simocyclinone D8 is a more potent inhibitor than novobiocin.

Potential applications: The CombiGyrase results benefit public health by providing a road to new antibiotics, which will help to combat infectious diseases.

Project Coordinator Prof. Dr Lutz Heide University of Tübingen Pharmazeutisches Institut Auf der Morgenstelle 8 72076 Tübingen, Germany Tel. +49 070712972460 Fax +07071295250 E-mail: [email protected] CRAB | 31 Combating resistance to antibiotics http://www.www.eucrab.org

BACKGROUND identification of novel stabilisation mod- Combating bacteria with antibiotics is an ules (toxin/antitoxin) and of their func- endless race because bacteria acquire tional characterisation (partly achieved); antibiotic resistance (AR) genes easily development of new molecu- from unknown environmental sources. An lar biological tools (expected). appropriate long-term public health objective would be to elucidate the molecular Potential applications: mechanisms behind the observed AR The application of state-of-the-art functional spread. The CRAB project explored a genomics will facilitate the translation of ge- mechanistic approach to combat AR. nomic data into novel products. Several of the novel approaches such as in situ monitoring Problem: of bacterial conjugation will likely lead to fur- Although mutations are responsible for ther developments with commercial potential. some specific cases of AR, the driv- ing force behind the problem of mul- Project Coordinator tiresistance to antimicrobials is gene Dr Didier Mazel acquisition by human pathogens. Institut Pasteur Département d structure et dynamique des génomes AIMS Unité Plasticité du Genome Bactérien 25 rue du Dr Roux The principal aim of CRAB was to explore 75724 Paris, France the mechanisms and process dynam- Tel. +33 140613284 ics at work in each of the dissemina- Fax +33 145688834 E-mail: [email protected] tion modules of the chain of AR genes dissemination — integrons, transposons, Partners conjugative plasmids and stability Dr Michael Chandler modules — in a concerted approach. Centre National de la Recherche Scientifique (CNRS) EXPECTED Toulouse, France AND OBTAINED RESULTS Prof. Fernando de la Cruz The results CRAB anticipates Universidad de Cantabria Santander, Spain and has achieved include: Dr Ferenc Olasz Agricultural Biotechnology Center determination of the model driv- Gödöllő, Hungary ing integron cassette evolution; Prof. Dr Ellen L. Zechner description of the different ways Universitaet Graz by which the three major classes Graz, Austria of insertion sequence (IS) acquire, Dr Laurence Van Melderen stabilise and vehicle AR genes; Université Libre de Bruxelles Gosselies, Belgium quantitative evaluation of the impact of IS elements on horizontal transfer within Dr Finbarr Hayes University of Manchester, and between chosen bacterial genera, Manchester, England, UK. showing that IS together with conju- Dr Philippe Gabant gative plasmid constitute a powerful Delphi Genetics SA combination for horizontal gene transfer; Charleroi, Belgium

 Project number: LSHM-CT-2005-019023  EC contribution: €1 795 500  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2006 32 | DRESP2

Role of mobile genetic elements in the spread of antimicrobial drug resistance

http://www.dresp2.com

BACKGROUND Project Coordinator Mobile DNA elements provide a major Dr. Marco R. Oggioni, Prof Gianni Pozzi, contribution to the spread of antimicrobial Dr. Gian Maria Rossolini LA.M.M.B. (Laboratorio di Microbiologia resistance allowing for recruiting new resist- Molecolare e Biotecnologia) ance genes in bacterial pathogens and fa- Dipartimento di Bilogia Molecolare cilitating their horizontal spread. While much Università degli Studi di Siena Policlinico Le Scotte (lotto 5, piano 1) is known about individual resistance genes 53100 Siena, Italy and mechanisms, very little is known about Tel. +39 0577233101 (Oggioni); +39 0577233430 their molecular epidemiology. The DRESP (Pozzi); +39 0577233326 (Rossolini) Fax +39 0577233334 project aimed at investigating these aspects. E-mail: [email protected]; [email protected]; [email protected] Problem: Partners Antibiotic resistance remains a major clini- Dr. David J. Farrell and Dr. Ian Morrissey cal and public health problem, and mobile GR Micro and Quotient Bioresearch Ltd DNA elements provide a major contribu- London, England, UK tion to the spread of antibiotic resistance. Dr. Stefania Stefani and Dr. Maria Santagati University of Catania AIMS Catania, Italy DRESP2 focused on the characterisation Dr. Fernando Baquero of the molecular mechanism(s) underly- and Dr.Juan Carlos Galan Ramón y Cajal Hospital ing mobility of genetic elements carry- Madrid, Spain ing antimicrobial resistance genes. Dr. Lars Sundström Uppsala University EXPECTED Uppsala, Sweden AND OBTAINED RESULTS Dr. Alex van Belkum An exceptional amount of data (e.g. ge- Erasmus University Rotterdam nomics, nomenclature) was produced and Rotterdam, Netherlands made available to the scientific community. Dr. Alessandra Carattoli and Dr. Annalisa Pantosti Istituto Superiore di Sanità Key contributions in this extensive list of Rome, Italy data include the description and application Dr. Patrice Nordmann of new techniques for molecular replicon University Paris XI typing of plasmids encoding resistance Le-Kremlin-Bicêtre, France to newer beta-lactams, and the descrip- Dr. Jose-Luis Martinez and Dr. Teresa M. Coque tion of antibiotics as signalling agents. Centro Nacional de Biotecnologia Madrid, Spain Potential applications: Dr. Balázs Libisch and Dr. Miklos Fuzi in vitro diagnostic medical device; National Center for Epidemiology Budapest, Hungary epidemiology of drug resistances; Dr. Timothy R. Walsh prediction of drug resistance emer- Cardiff University gence to novel compounds. Cardiff, Wales, UK

 Project number: LSHM-CT-2005-018705  EC contribution: €1 852 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2006 e-Bug | 33 Development and dissemination of a school antibiotic and hygiene education pack and website across Europe http://www.e-bug.eu

BACKGROUND development of a school pack e-Bug is a school educational resource template incorporating hygiene pack and website incorporating areas and prudent antibiotic use for of hygiene and prudent antibiotic use to use across European states; be developed and disseminated across development of a school educa- Europe. The teaching pack with work- tion website for 9-11 and 13-16 years sheets linking in with each country’s to improve health across the EU. national curriculum will be accompanied dissemination of packs and marketing by websites hosting games and inter- to collaborating partner countries. active quizzes. Results will be used to further modify and improve the pack and EXPECTED website to better meet the local needs. AND OBTAINED RESULTS The expected results include: The consortium consists of 10 associated countries (304 million) covering 42% of a report on background in- the European population with the highest formation covering: antibiotic use and those with large popula- how education about hygiene, tions, thus obtaining education amongst normal flora and prudent antibiotic a high percentage of high antibiotic user use are covered in the schools of countries. In total, this initiative will reach the associated partner countries; 47% of the European population. Website resources for adults and school aged children Problem: Public or school educa- In many European countries, antibi- tion campaigns in these ar- otic prescription rates are highest in eas and across Europe and if/ children. Within schools, respiratory and how these have been evaluated gastrointestinal infections are a major implementation strategies that cause of childhood illness with poor have been used in the countries respiratory and hand hygiene contribut- for educational resources. ing to increased spread of infection. evaluation reports covering: AIMS the ease of use and impact of the The aims of the e-Bug project include: pack on children’s knowledge will be assessed in three associated exchange of information and experi- partner countries through ques- ences of good practice (EU priority 1.6 tionnaires and focus groups; & 1.8) within the educational curricu- report on ease of accessibil- lum, public campaigns and websites ity and impact of the website with associated partner countries;

 Project number: 2 0 05211  EC contribution: €1 865 358  Duration: 39 months  Starting date: 15 June 2006 34 | e-Bug

Potential applications: Prof. Pierre Dellamonica The e-Bug pack and website will reinforce Hospital l’Archet I Nice, France an awareness of the benefits of antibiotics and will teach about prudent use and how Dr. Julius Weinberg Institute of Health Sciences inappropriate use can have an adverse London, England, UK effect on an individual’s good bugs and Prof. Jenny Kourea-Kermastinou antibiotics resistance in the community. National School of Public Health Athens, Greece Project Coordinator Prof. Giuseppe Cornaglia Dr Cliodna A.M. McNulty University of Verona Primary Care Unit Verona, Italy Health Protection Agency Dr Pawel Grzesiowski Microbiology Department National Institute of Public Health Gloucestershire Royal Hospital Warsaw, Poland Great Western Road Gloucester, GL1 3NN, England, UK Dr Antonio Brito Avo E-mail: [email protected] Oearis Health Centre Lisbon, Portugal Partners Dr Jose Campos Instituto de Salud Carlos III Lead Administrator Madrid, Spain Jennifer Stubbs Health Protection Agency Collaborating Partners: Gloucester, England, UK Dr Arjana Tambic Pack Developer University Hospital for Infectious Diseases Dr Donna M. Lecky Zagreb, Croatia Health Protection Agency Gloucester, England, UK Prof. Pentti Huovinen National Public Health Institute Web Lead Turku, Finland Dr Patty Kostkova Institute of Health Sciences Dr Gabor Ternak London, England, UK University of Pécs, School of Medicine Pecs, Hungary Web designer David Farrell Dr Robert Cunney Institute of Health Sciences Health Protection Surveillance Centre London, England, UK Dublin, Ireland Dr Sandra Berzina Associate Partners: Latvian University Prof. Herman Goossens Riga, Latvia University of Antwerp Dr Rolanda Valinteliene Antwerp, Belgium Institute of Hygiene Vilnius, Lithuania Dr Jiri Benez Bulovka University Hospital Dr Tomas Tesar Prague, Czech Republic Comenius University Bratislava, Slovakia Dr Dominique L. Monnet National Center for Antimicrobials Dr Marko Pokorn & Infection Control (SSI) University Medical Centre Ljubljana Copenhagen, Denmark Ljubljana, Slovenia EACCAD | 35 European approach to combat outbreaks of Clostridium difficile associated diarrhoea by development of new diagnostic tests http://www.cdiff.nl

BACKGROUND rapid membrane immunoassays Clostridium difficile-associated disease for detection of the target in patient (CDAD) has become the most frequent material and in bacterial isolates. nosocomial infection in many Euro- 3. Validation of new developed pean hospitals. Central to the control of tests for clinical diagnostics epidemics are the deployment of assays and strain characterisation. able to rapidly diagnose and monitor the presence and spread of the organism. Potential applications: No such tests currently exist for these European guidelines will be formulated to new hypervirulent C. difficile strains. The diagnose CDAD and to combat out- EACCAD project sought to develop the breaks. The introduction of these tests urgently required rapid, diagnostic assays and European guidelines increase the in close collaboration with three small awareness of CDAD as an important and medium-sized enterprises (SMEs). nosocomial infection and will be of help to prevent the development of large out- Problem: breaks by new hypervirulent variants. C. difficile is resistant to various antibiotics; it capitalises on the ensuing dis- Project Coordinator ruption of the normal intestinal flora to Dr. Ed J. Kuijper colonisation and causes disease. The Leiden University Medical Center Department of Medical Microbiology effects of CDAD are devastating, both P.O. Box 9600 in terms of morbidity/mortality and the 2300 RC Leiden, Netherlands high costs of disease management. Tel. + 31 715263574 Fax + 31 715248148 E-mail: [email protected] AIMS The main aim of EACCAD was the Partners recognition of suitable targets and Dr Maja Rupnik University of Maribor development of a commercial rapid test Maribor, Slovenia that would distinguish variant hyper- Prof. Nigel Minton virulent and antibiotic resistant strains University of Nottingham from ordinary C. difficile strains. Nottingham, England, UK Dr Paola Mastrantonio Istituto Superiore di Sanità (ISS) EXPECTED Rome, Italy AND OBTAINED RESULTS Prof. Cristoph von Eichel-Streiber 1. Recognition of targets for new diag- tgcBiomics GmbH nostic tests by characterisation of Mainz, Germany hypervirulent and drug-resistant C. Dr Thierry Leclipteux difficile strains. The targets are based Coris BioConcept Gembloux, Belgium on toxins, toxin coding regions, or Dr Guus Simons other unique genes of C. difficile. Pathofinder BV 2. Availability of molecular tests and Maastricht, Netherlands

 Project number: LSHM-CT-2006-037870  EC contribution: €1 771 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 December 2006 36 | EAR Effects of antibiotic resistance on bacterial fitness, virulence and transmission

BACKGROUND development and achieve a reversal of A major factor affecting the emergence and the rising tide of resistance in society. survival of resistant strains is the biological Thirdly, the methodology and approaches cost of resistance. The EAR consortium will make it possible to identify particular aimed to identify antibiotic targets and attributes in high-risk resistant bacteria. antibiotics for which the resistance mechanisms have the most negative effects on Potential applications: bacterial fitness. The partners experi- The deliverables of EAR will aid in the mentally examined and defined in several development of guidelines for the clinical medically important species how fitness, use and regulation of antibiotics, which virulence and transmission are affected may help free resources for other im- by different types of antibiotic resistance. portant health issues of EU citizens.

Problem: Project Coordinator Prof. Dan I. Andersson Antibiotic resistance repre- Uppsala University sents a major public health con- Department of Medical Biochemistry and cern and economic problem. Microbiology Box 582, BMC 751 23 Uppsala, Sweden AIMS Tel. +46 184714175 The aims of the EAR project include: Fax +46 18509876 E-mail: [email protected]

experimentally determining how dif- Partners ferent types of antibiotic resistances Dr Niels Frimodt-Møller The National Centre for Surveillance affect fitness (growth and survival and Control of Infectious Diseases within and outside hosts) of several Copenhagen, Denmark pathogenic bacterial species; Prof. Diarmaid Hughes determining if the fitness costs of Uppsala University Uppsala, Sweden resistance can be reduced by mutation and/or environmental conditions; Dr Fernando Baquero Ramón y Cajal University Hospital (IMSALUD) developing animal experimental Madrid, Spain models to study the impact of re- Prof. Stephen H. Gillespie sistance on transmission rates; University College London London, England, UK EXPECTED Dr Jose Luis Martinez Centro Nacional de Biotecnología AND OBTAINED RESULTS Madrid, Spain Firstly, the results will provide the experimen- Prof. Erik C. Böttger tal knowledge required to model and perform University of Zurich risk assessment for the development and Zurich, Switzerland spread of resistance to any given antibiotic. Prof. Patrice Courvalin Secondly, the achievements accomplished Institut Pasteur Paris, France here will form the knowledge base required to formulate and interpret intervention strate- Dr Tore Duvold LEO Pharma gies that seek to reduce the rate of resistance Ballerup, Denmark

 Project number: LSHM-CT-2005-518152  EC contribution: €2 755 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 December 2005 EARSS | 37 The European antimicrobial resistance surveillance system http://www.rivm.nl/earss

BACKGROUND OBTAINED RESULTS The European Antimicrobial Resistance For pathogens (Streptococcus pneumo- Surveillance System (EARSS), is an inter- niae, Staphylococcus aureus, Escherichia national network of national surveillance coli, and Enterococcus faecalis/faecium) systems that collects comparable and causing invasive infections, resistance validated antimicrobial susceptibility data levels are available for important groups of for public health purposes. The project per- antimicrobials from 27 European coun- forms ongoing surveillance of antimicrobial tries. In the EARSS annual report 2001, susceptibility in Streptococcus pneumo- results are described in detail for all four niae, Staphylococcus aureus, Escherichia pathogens collected in 2001. Aggre- coli, and Enterococcus faecalis/faecium gated information is directly available to causing invasive infections, and moni- healthcare workers, policymakers, and tors variations of antimicrobial resistance a wider public, at www.earss.rivm.nl. (AMR) in time and from place to place. Potential applications: Problem: Policies to combat resistance should AMR is an emerging public health problem be specifically tailored to country and with local, national, and international dimen- hospital level. The results, as presented in sions as described in ‘the Copenhagen the EARSS annual report 2001, empha- Recommendations’. Antimicrobial resistance sise the need to implement the Council is clearly an emerging problem. However, Recommendations on the Prudent Use the precise impact of this problem is less of Antibiotics in Human Medicine. As laid clear to the European and scientific commu- down in the Council Recommendations, it nity. Before being able to quantify the impact has recently been decided that multidisci- on public health it is necessary to have more plinary organisations, called Intersectorial comparable surveillance data available. One Coordinating Mechanisms (ICMs), will of the recommendations made at the EU be established at the national level. The Conference ‘The Microbial Threat’ in 1998 ICMs will be responsible for information was that a European surveillance system of exchange and cooperation between the antimicrobial resistance should be set up, parties involved at the national level. therefore EARSS has been established. Project Coordinator AIMS Dr Edine W. Tiemersma EARSS aimed to obtain comparable and National Institute for Public Health and the Environment reliable AMR data of main indicator patho- P.O. Box 1 gens in Europe so as to monitor AMR in 3720 BA Bilthoven, Netherlands Tel. +31 30 27 43 096 (M, T, Th, F) time and from place to place. It also aimed Fax +31 30 27 44 409 to assess risk factors for AMR and to enable policymakers and healthcare workers to monitor the impact of their interventions.

 Project number: 2003212  EC contribution: 734142 €  Duration: 36 months  Starting date: 1 Septembre 2003 38 | EARSS

Iceland (IS) Project leader K. Kristinsson Dr Hajo Grundmann National Institute for Public Health and the Israel (IL) Environment R. Raz P.O. Box 1 Italy (IT) 3720 BA Bilthoven, Netherlands A. Pantosti Tel. +31 30 27 44 239 P. D ‘Ancona Fax +31 30 27 44 409 Latvia (LV) Partners A. Balode Overview of EARSS National Lithuania (LT) Representatives by country: J. Miciuleviciene

Austria (AT) Luxembourg (LU) H. Mittermayer R. Hemmer W. Koller Malta (MT) Belgium (BE) M. Borg H. Goossens Netherlands (NL) E. Hendrickx E. Tiemersma Bulgaria (BG) A. de Neeling B. Markova Norway (NO) Croatia (HR) A. Hoiby S. Kalenic G. Simonsen A.Tambic Poland (PL) Andrasevic W. Hryniewicz Cyprus (CY) Portugal (PT) D. Bagatzouni M. Caniça Czech Rep. (CZ) Romania (RO) P. Urbaskova I. Codita Denmark (DK) Slovakia (SK) D. Monnet L. Langsadl R. Skov Slovenia (SI) Estonia (EE) M. Mueller-Premru P. Naaber J. Kolman Finland (FI) Spain (ES) O. Lyytikäinen F. Baquero A. Nissinen J. Campos France (FR) Sweden (SE) B. Coignard B. Liljequist V. Jarlier Turkey (TR) Germany (DE) D. Gür W. Witte K. Heckenbach United Kingdom (UK) A. Johnson, R. Hill Greece (GR) A. Tsakris (England & Wales) A. Vatopoulus H. Hughes Hungary (HU) (Northern Ireland) M. Füzi A. Eastaway Ireland (IE) (Scotland) D. Igoe O. Murphy ERAPharm | 39

Environmental risk assessment of pharmaceuticals http://www.erapharm.org

BACKGROUND (2) on aquatic and terrestrial or- ERAPharm aimed to improve existing ganisms, at single species, knowledge and methods for evaluat- population and community ing potential risks posed by human and level using laboratory, micro- and veterinary pharmaceuticals to the en- meso-cosm and field studies. vironment. The consortium addressed The effects of antibiotics were in- the different aspects of environmental vestigated in terrestrial and aquatic risk assessment (ERA) of pharmaceu- microbial microcosm studies. ticals, including exposure modelling. Potential applications: Problem: ERAPharm is expected to contribute to the The widespread detection of pharmaceu- establishment of more targeted and more ticals in surface waters, soils and ground- standardised environmental risk assess- water worldwide has raised major concerns ment procedures for pharmaceuticals. about the potential impact of these bioactive substances on the environment. Project Coordinator Dr Thomas Knacker AIMS ECT Oekotoxikologie GmbH Böttgerstrasse 2-14 ERAPharm aimed to advance exist- 65439 Flörsheim/M., Germany ing knowledge and procedures for the Tel. +49 6145956411 environmental risk assessment of hu- Fax +49 6145956499 man and veterinary pharmaceuticals. E-mail: [email protected] Partners OBTAINED RESULTS Dr Jason R. Snape Analytical methods were developed and AstraZeneca UK Ltd adapted to determine selected phar- Brixham Environmental Laboratory maceuticals in environmental matrices. Brixham, England, UK Three new scenarios were identified Prof. John Sumpter as being insufficiently covered in the Brunel University Uxbridge, England, UK existing framework for the ERA of veterinary pharmaceuticals, despite being Dr Thomas Ternes relevant for veterinary pharmaceuticals. Bundesanstalt für Gewässerkunde Koblenz, Germany The effects of a set of human and veterinary pharmaceuticals were studied: Dr Jeanne Garric Centre National du Machinisme Agricole du (1) in in vitro and low complex- Genie Rural des Eaux et des Forêts (Cemagref) ity bioassays, and Lyon, France

 Project number: SSPI-CT-2003-511135  EC contribution: €2 797 198  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 October 2004 40 | ERAPharm

Dr Alistair Boxall University of York York, England, UK Prof. Bent-Halling-Sørensen Copenhagen University Copenhagen, Denmark Dr Kathrin Fenner Swiss Federal Institute of Aquatic Science and Technology (Eawag) Duebendorf, Switzerland Dr Christian Zipper Geotechnisches Institut AG Bern, Switzerland Dr Heike Schmitt Utrecht University Utrecht, Netherlands Dr José Tarazona Instituto Nacional de Investigación y Tecnologia Agraria y Alimentaria (INIA) Madrid, Spain Dr John Jensen Aarhus Universitet Aarhus, Denmark Dr Bettina Rechenberg Umweltbundesamt Dessau, Germany Prof. Mark Servos University of Waterloo Waterloo, Ontario, Canada ESAC | 41

European surveillance of antimicrobial consumption http://www.esac.ua.ac.be

BACKGROUND EXPECTED In 2001, the European Commission AND OBTAINED RESULTS funded the ESAC project which aimed The results anticipated by ESAC include: to collect comparable and reliable data on antibiotic use in Europe in ambulatory regional maps of antibi- and hospital care from publicly available otic use in Europe; sources, and assess the time trends in hospital and individual patient con- human exposure to antibiotics. In the sumption data linked with DRG second phase of the project (2004/07), (Disease Related Groups); the ESAC partners consolidated the data. expansion of health indica- In 2006, 34 countries including the 27 EU tors of antimicrobial use; Member States, 2 Candidate Countries assessment of the effects of socioeco- and 5 other nations participated in ESAC. nomic determinants on antimicrobial consumption of European countries. ESAC data have been used to explain the variation of antibiotic resistance and to Potential applications: assess the impact of intervention cam- More and more countries have imple- paigns to reduce antibiotic prescribing. mented or will implement actions to control antimicrobial resistance through Problem: the rational use of antibiotics. Their impact Antibiotic resistance is a major European will be monitored based on Defined and global public health problem, and inter- Daily Doses per 1000 inhabitants national efforts are needed to counteract the per day (DID)and other indica- emergence of resistance. There is a wealth tors of antibiotic use. of information on the prevalence of resist- The different sub-projects on am- ance in human pathogens, and these data bulatory care, hospital care, nursing show that there are substantial geographic homes and socioeconomics will sub- differences in the proportion of resistance stantially deepen our interpretation of to various classes of antibiotics in Europe. variation in antibiotic resistance.

AIMS Project Coordinator The overall aim of ESAC was to consolidate Prof. Herman Goossens the continuous collection of comprehen- University of Antwerp – Campus Drie Eiken Vaccine and Infectious Diseases Institute sive antimicrobial consumption data, from Medical microbiology ambulatory and hospital care, from the Universiteitsplein 1 2610 Antwerp, Belgium 27 Member States, 3 EEA/EFTA and 3 can- [email protected] didate countries (Croatia, Former Yugosla- vian Republic of Macedonia and Turkey).

 Project number: 2003211  EC contribution: € 880606.00  Duration: 36 months  Type: Surveillance Project  Starting date: 1 December 2004 42 | ESAC

Partners Dr. Uga Dumpis Dr. Helmut Mittermayer University of Latvia Krankenhaus der Elisabethinen Linz Riga, Latvia Linz, Austria Dr. Rolanda Valinteliene MD. Erik Hendrickx Institute of Hygiene Scientific Institute of Public Health Vilnius, Lithuania Brussels, Belgium Dr. Marcel Bruch Dr. Boyka Markova Direction de la Santé (Ministère de la Santé) University Hospital ‘Alexandrovska’ Luxembourg, Luxembourg Sofia, Bulgaria MD. Michael Borg Dr. Arjana Andrasevic Infection Control Unit, Mater Dei Hospital University Hospital for Infectious Diseases Msida, Malta Zagreb, Croatia Dr. Hege Salvesen Blix Dr. Antonis Kontemeniotis Norwegian Institute of Public Health Pharmaceutical Services of the Ministry Oslo, Norway of Health of Cyprus Dr. Waleria Hryniewicz Nicosia, Cyprus National Institute of Public Health Dr. Jiri Vlcek Warsaw, Poland Charles University of Prague Dr. Inês Teixeira Hradec Kralove, Czech Republic Instituto Nacional da Farmacia e do Dr. Niels Frimodt-Møller Medicamento Statens Serum Institut Lisbon, Portugal Copenhagen S, Denmark Dr. Băicuş Anda Dr. Ly Rootslane National Institute of Research Development State Agency of Medicines Bureau for Microbiology and Immunology of Drug Statistics Bucharest, Romania Tartu, Estonia Dr. Svetlana Ratchina Dr. Pentti Huovinen Smolensk State Medical Academy National Public Health Institute Smolensk, Russia Turku, Finland Dr. Viliam Foltan Dr. Milena Petrovska Comenius University Microbiology and Parasitology Medical Faculty Bratislava, Slovakia Skopje, FYROM Dr. Milan Cizman Dr. Philippe Cavalié University Medical Centre Llubljana, Department Direction de l’évaluation de la publicité, des of Infectious Diseases, Japljeva 2, SI-1525 produits cosmétiques et biocides DEPPCB Ljubljana, Slovenia Saint-Denis, France Dr. José Campos Dr. Winfried V Kern Instituto Carlos III Ministry of Health University Hospital – Abteilung Medizin 2 Mazadahonda-Madrid, Spain Freiburg, Germany Dr. Gunilla Skoog Prof. Helen Giamarellou The Swedish Institute for Infectious Disease Sismanoglio Hospital Control Marousi, Attica, Greece Solna, Sweden Dr. Gabor Ternak Prof. Giorgio Zanetti County Hospital Service de Médicine Préventive Hospitalière Pécs, Hungary Lausanne, Switzerland Prof. Karl G. Kristinsson Dr. Margreet Filius Landspitali – University Hospital Erasmus University Medical Centre Rotterdam Reykjavik, Iceland Rotterdam, Netherlands Dr. Robert Cunney Dr. Serhat Unal Sta National Disease Surveillance Centre Hacettepe University Dublin 1, Ireland Ankara, Turkey Dr. Raul Raz Dr. Peter Davey Ha’Emek Medical Center Ninewells Hospital Afula, Israel Dundee, Scotland - UK Dr. Pietro Folino Agenzia Italiana del Farmaco Rome, Italy ESSTI | 43

European surveillance of sexually transmitted infections http://www.essti.org

BACKGROUND on STI surveillance, lab diag- Sexually transmitted infections (STIs) in nostics and STI clinical manage- Europe are a major public health threat. ment to network participants; Their increasing incidence; adverse impact use of ESSTI website for in- on individual and public health; substantial formation dissemination. economic costs; and emerging antimicrobial resistance have increased the need EXPECTED RESULTS for pan-European approaches to their 1. Estimates of resistance to antimi- control. The ESSTI (European Surveillance crobial agents used for the therapy of Sexually Transmitted Infections) Network of gonorrhoea across Europe. aims to develop and coordinate epidemio- 2. Comparability of methods for deter- logical and laboratory surveillance of STIs mining susceptibility to antimicrobial in the European region in order to better agents for Neisseria gonorrhoeae. inform STI prevention, care and control. 3. Establishment of a panel of control strains for use in labo- Problem: ratories across Europe. The increasing incidence of gonococcal infections is of concern due to the acquisition Potential applications: of resistance to antimicrobials by the caus- Collaboration between the laboratories in ative bacterium Neisseria gonorrhoeae. this network should establish a European Antimicrobial resistance has implications Gonococcal Surveillance Programme for the treatment of gonorrhoea and there- (Euro_GASP) that will monitor resistance fore surveillance has a key role in inform- to therapeutic agents across Europe and ing about national treatment guidelines. inform individual patient management and the production of therapeutic guidelines. AIMS Specific objectives include: Project Coordinator Prof. Cathy Ison Health Protection Agency operation and development of 61 Colindale Avenue the ESSTI network with EU Mem- London, NW9 5EQ, England, UK ber States, EFTA/EEA, Turkey; E-mail: [email protected] extension of ESSTI_ALERT, the Europe- Partners an early warning system for unexpected Dr Reinhild Strauss and adverse STI transmission events; Federal Ministry for Health and Women implementation of a European Gono- Vienna, Austria coccal Antimicrobial Susceptibility Dr. Angelika Stary Surveillance Project (Euro_GASP); Outpatients’ Centre for Diagnosis of Infectious Venero-Dermatological Diseases delivery of training programmes Vienna, Austria

 Project number: 2004210  EC contribution: €1 353 597,88  Duration: 36 months  Type: DG-SANCO  Starting date: 1 January 2006 44 | ESSTI

Dr. André Sasse Dr. Jackie Maistre Melillo Scientific Institute of Public Health Department of Public Health Brussels, Belgium Msida, Malta Dr. Tania Crucitti Dr. Marianne van der Sande Institute of Tropical Medicine National Institute of Public Health Antwerp, Belgium & the Environment Dr Chrystalla Hadjianastassiou Bilthoven, Netherlands Medical and Public Health Services, Dr. Ineke Linde Ministry of Health GGD Amsterdam Nicosia, Cyprus Amsterdam, Netherlands Dr. Susan Cowan and Steen Hoffman Dr. Hilde Kløvstad and Dr. Vegard Skogen Statens Serum Institut Norwegian Institute of Public Health Copenhagen S, Denmark Oslo, Norway Dr. Anneli Uusküla Dr. Slawomir Majewski and Dr. Magdalena Tartu University Clinics Malejczyk Tartu, Estonia Warwaw School of Medicine Dr. Rutta Voiko Warsaw, Poland West Tallinn Central Hospital Dr. Jacinta Azevedo Tallinn, Estonia General Directorate of Health Dr. Eija Hiltunen-Back Lisbon, Portugal National Public Health Institute Dr. Maria José Borrego Helsinki, Finland Instituto Nacional de Saude Dr Ricardo Jorge Dr. Véronique Goulet Lisbon, Portugal Institut de Veille Sanitaire Dr. Jan Mikas Saint-Maurice, France National Public Health Agency of the Slovak Dr. Patrice Sednaoui Republic Institut Alfred Fournier Bratislava, Slovakia Paris, France Dr. Alenka Andlovic Dr. Osamah Hamouda University of Ljubljana Robert Koch Institut Ljubljana, Slovenia Berlin, Germany Dr. Irena Klavs Prof. Peter Kohl Institute of Public Health of the Republic of Vívantes Klinikum Neukölln Slovenia Berlin, Germany Ljubljana, Slovenia Dr. Vasileia Konte Hellenic Centre for Infectious Disease Control Dr. Mercedes Diez and Dr. Julio Vazquez Athens, Greece Instituto de Salud Carlos III Madrid, Spain Dr. Eva Tzelepi Hellenic Pasteur Institute Dr. Inga Velicko and Dr. Anders Blaxhult Athens, Greece Swedish Institute for Infectious Disease Control Solna, Sweden Dr. Guðrun Sigmundsdottir Directorate of Health Dr. Hans Fredlund Seltjarnarnes, Iceland Swedish Reference Laboratory for Pathogenic Dr Aidan O’Hora Neisseria Health Protection Surveillance Centre Orebro, Sweden Dublin 1, Ireland Dr. Peyman Altan Dr. Helen Barry General Directorate of Primary Care Services, St James Hospital Ministry of Health Dublin 8, Ireland Sihhiye-Ankara, Turkey Dr. Paola Stefanelli and Dr. Barbara Suligoi Dr. Gwenda Hughes Istituto Superiore di Sanità Health Protection Agency, Centre for Infections Rome, Italy London, England, UK Dr. Judite Pirsko and Dr. Elvira Lavrinovica Dr. Lesley Wallace State Centre of Sexually Transmitted Health Protection Scotland and Skin Diseases Glasgow, Scotland, UK Riga, Latvia Dr. Hugh Young Dr. Christopher Barbara Scottish Neisseria gonorrhoeae Reference St Luke’s Hospital Laboratory G’Mangia, Malta Edinburgh, Scotland, UK ET-PA | 45 Enabling techniques for the development of a novel class of protein antibiotics http://www.et-pa.org

BACKGROUND the class of REPP molecules as antibiot- Antibiotics’ resistance to pathogens is a ics. Lead substances for further preclinical major threat to public health and safety, development were expected. The ET-PA increasing the risk of mortality, especially in consortium has defined that for a suc- hospital settings. This issue also includes cessful targeting of prokaryotic pathogens preparedness to deal with bio-terrorism. by REPP antibiotics, these molecules Currently, the antibiotics market is dominat- must clearly accomplish four tasks cross ed by small molecule classes, which all face the outer cell wall barriers of bacteria increased drug resistance and require prod- and bind to the membrane surface; uct differentiation. While this remains a primary focus in antibiotics development, new 1. enter into the cytoplasm by concepts for entirely new classes of sub- translocating or otherwise crossing stances for the treatment of bacteria, fungi, the cytoplasmic membrane; viruses and protozoa are urgently needed. 2. fold the enzymatic portion to the active form, a process whose rate limiting AIMS step in natural REs is mainly defined ET-PA aimed to develop an open, generic by the rate of the dimerisation; platform to enable the development of 3. specifically bind to and cut DNA a new class of protein-antibiotics. The damaging the bacterial genome. key technology (REPPs) is based on a principle that is proprietary to one of the Project Coordinator participating small and medium-sized Christian Kuehne Adriacell Srl Trieste enterprises (SMEs), and consists of Area Science Park rationally modified, single-chain class II Sede Laboratorio Basovizza, S.S. 14, Km 163.5 34012 Trieste, Italy restriction enzymes (REs) fused to cell Tel. +39 0403757770 penetration peptide (PP) sequences that Fax +39 0403757773 selectively allow microbial cell penetration. E-mail: [email protected] The consortium sought to fuse an ap- Partners propriate cell PP sequence to an engi- Dr Ales Strancar neered RE that includes both subunits BIA Separations d.o.o. in a single chain, so as to produce a Ljubljana, Slovenia ‘REPP’ construct capable of microbial Prof. Dr Peter Laggner cell penetration and autonomous fold- Hecus X-Ray Systems GmbH ing to an active unit within the cell. Graz, Austria Prof. Renato Gennaro University of Trieste EXPECTED Trieste, Italy AND OBTAINED RESULTS Prof. Dr Hans-Georg Sahl The major milestone was to provide a clear University of Bonn proof of concept for the introduction of Bonn, Germany

 Project number: COOP-CT-2005-018191  EC contribution: €945 120  Duration: 24 months  Type: Horizontal Research Activities involving SMEs - Cooperative Research Project  Starting date: 1 August 2005 46 | EU-IBIS

Invasive bacterial infections surveillance in European Union

http://www.euibis.org

BACKGROUND focusing on a wider collabora- Standardisation of epidemiological and tion with non-EU countries laboratory methodologies across the EU and Candidate Countries. allows valid overviews and comparisons to be drawn on the epidemiology of invasive EXPECTED Haemophilus influenzae (H. influenzae) AND OBTAINED RESULTS and Neisseria meningitidis (N. menin- The EU-IBIS network contributed to gitidis) diseases. These two diseases strengthening disease-specific surveillance are both rare, and the EU-IBIS project in the EU. Through the use of standard EU allowed the pooling of data to increase case definitions and an agreed minimum the power of an epidemiological analysis. dataset, the comparability of surveillance data allows valid comparisons to be Problem: drawn across the EU. Improved labora- The bacteria N. meningitidis and H. tory capacity for diagnosis and charac- influenzae are an important cause of terisation of circulating organisms will also invasive disease, including meningitis, contribute to making valid comparisons septicaemia and epiglottitis, across between countries possible, and will Europe. These bacterial infections con- enable accurate reporting on emerging tribute to morbidity and mortality, par- strains, or rapid reporting. A number of ticularly in young children, and represent countries with unreconciled datasets will be an important public health problem. encouraged to work towards full reconcili- ation of their clinical and laboratory data. AIMS This will improve the data contributed The objectives of the project included: to EU-IBIS, but will also have beneficial value to the individual countries. improving the epidemiological information on invasive menin- Improvements in surveillance data have gococcal and Haemophilus influ- already occurred within EU-IBIS par- enzae disease within the EU; ticipant countries, and will continue to be improving the laboratory capacity to seen, especially in Accession Countries. accurately characterise the isolates The standardised epidemiological and of H. influenzae and N. meningitidis; microbiological data gathered by EU-IBIS evaluating the impact of vaccination with give the ability to detect whether changes conjugate vaccines on the epidemiology in disease epidemiology are driven by of H. influenzae and N. meningitidis; environmental factors or vaccine impact. comparing the impact of vaccination with conjugate vaccines produced Equally, the network enables a concerted by different manufacturers and ac- response to such changes with appropri- cording to different schedules; ate surveillance strategies or public health

 Project number: 2003202  EC contribution: € 665.877  Duration: 36 months  Type: Health project  Starting date: 2 October 2003 EU-IBIS | 47

interventions. This was demonstrated Partners by the establishment of two short-term Please note that the complete Partners N. meningitidis rapid reporting systems names and addresses are available on the project website (www.euibis.org). over the lifetime of the project; a sentinel W135 reporting system following the Hajj Dr Reinhild Strauss Federal Ministry for Health, 2000 outbreak, and a B:2a/B:2b rapid Family and Youth, Austria reporting system to identify instances of Dr Sigrid Heuberger capsule switching following the introduc- Austrian Agency for Food tion of meningococcal C. vaccine. and Health Safety, Austria Dr Germaine Hanquet Attainment of standardised, qual- Louis Pasteur, Belgium ity surveillance data for H. influenzae Mrs Françoise Carion Scientific Institute of Public Health, Belgium and N. menigitidis throughout the EU provides a platform for other studies of Dr Pavla Krizova and Dr Vera Lebedova National Institute of Public Health, meningococcal disease and H. influen- Czech Republic zae. This has already been seen in the Dr Kåre Mølbak, Dr Jens Jørgen Christensen, EU-MenNet-EU-IBIS collaboration. Dr Margit S. Kaltoft Statens Serum Institut, Denmark Potential applications: Dr Mary Slack and Dr Mary Ramsay This project will allow the more rational Health Protection Agency, England, UK development of vaccine policy in Europe Prof. Andrew Fox and ensure that this policy is evidence- Health Protection Agency North West Laboratory, England, UK based. Rapid dissemination of changes Dr Kuulo Kutsar and Dr Unna Jöks in the epidemiology of an infection which Health Protection Inspectorate, Estonia may have public health significance is Dr Petri Ruutu, Helena Käyhty, Maija Leinonen possible through the established EU-IBIS National Public Health Institute, Finland network. The standards set by EU-IBIS Dr Isabelle Parent du Châtelet for epidemiological surveillance and for and Dr Agnès Lepoutre methods used in reference laboratories Institut de Veille Sanitaire, France provide models of good practice from Dr Muhamed-Khier Taha which EU Member States, Candidate Institut Pasteur, France Countries and non-EU countries can Dr Walter Hass learn. Early dissemination of advances Dep Infecktions Epidemiologie, Germany in therapy and in public health control Prof. Dr Matthias Frosch and Dr Ulrich Vogel Institute for Hygiene and Microbiology, Germany measures can be facilitated through this network, which can lead to harmonisation Prof. Jenny Kourea-Kremastinou and Dr Georgina Tzanakaki of guidance on meningococcal disease. National School of Public Health, Greece Dr Miklós Füzi Project Coordinator Johan Bela National Centre for Epidemiology, Manny Chandra and Mary Ramsay Hungary HPC Centre for Infections Dr Thorolfur Gudnason Immunisation Department Centre for Infectious Disease Control, Iceland 61 Colindale Avenue London, England, UK Dr Hjordis Hardottoir Tel: +44.208327.7085 Institute of Laboratory Medicine, Iceland Fax: +44.208200.7868 E-mail: [email protected] Dr Suzanne Cotter E-mail: [email protected] Health Protection Surveillance Centre, Ireland 48 | EU-IBIS

Prof. Mary Cafferkey Dr A. Philip Zucs and Children’s University Hospital, Ireland Dr Hans-Peter Zimmermann Swiss Federal Office of Public Health, Dr Stefania Salmaso, Dr Paola Mastrantonio, Switzerland Dr Marta Ciofi degli Atti, Dr Marina Cerquetti Istituto Superiore di Sanità, Italy Dr Béatrice Ninet Hôpitaux Universitaires de Genève, Switzerland Dr Irina Lucenko Public Health Agency, Latvia Dr Peter McIntyre Children’s Hospital at Westmead and University Dr Grazina Rimseliene of Sydney, Australia Centre for Communicable Disease Prevention and Control, Lithuania Prof. Lyn Gilbert ICPMR, Westmead Hospital, Australia Dr Pierrette Huberty-Krau Inspection Sanitaire, Luxembourg Prof. Geoff Hogg University of Melbourne, Australia Dr François Schneider Laboratoire National de Santé, Luxembourg Dr Françoise Crokaert Institut Jules Bordet, Belgium Dr Jackie Maistre Melillo Department of Public Health, Malta Prof. Henri Dabernat Centre Hospitalier Universitaire de Toulouse, Dr Hester de Melker and Sabine de Greeff France National Institute of Public Health and the Environment, Netherlands Dr Anette Siedler Robert Koch Institute, Germany Dr Øistein Løvoll, Prof. Dominique A. Caugant, Dr Arne E. Hoiby Prof. Dr Med Heinz-J. Schmitt Norwegian Institute of Public Health, Norway and Dr Britta Gröndahl Johannes Gutenberg-Universitat, Germany Prof. Andrzej Zielinski National Institute of Hygiene, Poland Prof. Marie Theodoridou and Dr Anastasia Pangalis Prof. Waleria Hryniewicz ‘Aghia Sophia’ General Children’s Hospital, and Dr Anna Skoczynska Greece National Institute of Public Health, Poland Prof. Ron Dagan Dr Laurinda Queirós Soroko University Medical Centre Centro Regional de Saúde Pública de Norte, Portugal Snieguole Dauksiene National Public Health Investigation Centre, Dr Maria João Simões and Dr Paula Lavado Lithuania Instituto Nacional de Saúde Dr Ricardo Jorge, Portugal Dr Lodewijk Spanjaard and Dr Arie van der Ende Ms Barbara Denham Academic Medical Centre, Netherlands Stobhill Hospital, Scotland, UK Dr Claire Cameron and Fiona Johnston Dr Margareta Sláčiková and Dr Alena Health Protection Scotland, Scotland, UK Vaculiková Public Health Authority of the Slovak Republic, Dr Elena Nováková Slovakia Regional Public Health Authority, Slovakia Dr Alenka Kraigher and Dr Metka Paragi Institute of Public Health Slovenia, Slovenia Dr Rosa Cano Portero, Dr Julio Vazquez, Dr Jose Campos Instituto de Salud Carlos III, Spain Dr Rose-Marie Carlsson, Prof. Birgitta Henriques Normark, Margareta Löfdahl Swedish Institute for Infectious Disease Control, Sweden Prof. Per Olcén and Prof. Hans Fredlund National Reference Laboratory for Pathogenic Neisseria, Sweden EUCAST | 49

European committee on antimicrobial susceptibility testing http://www.eucast.org

BACKGROUND OBTAINED RESULTS EUCAST was initiated by the European 1. Standard operating procedures (SOP) Society of Clinical Microbiology and Infec- regulating the cooperation between tious Diseases (ESCMID) and the national EUCAST and EMEA is operative. breakpoint committees in Europe to give 2. Breakpoints for several new Europe uniform breakpoints for antimi- drugs have been determined. crobial susceptibility testing. EUCAST 3. Breakpoints for existing drugs have harmonised breakpoints for all existing an- been harmonised for aminoglycosides, timicrobials at the end of 2008. Moreover, glycopeptides, fluoroquinolones, through the cooperation between EUCAST linezolid, carbapenem, aztreonam, and EMEA, several new antimicrobi- cephalosporines, macrolides, als have received European breakpoints penicillins and miscellaneous drugs. through the EUCAST breakpoint process. 4. All cooperation (EFSA, EMEA, EARSS etc) is operative. Problem: 5. Subcommittees on antifungal There is a lack of uniform antimicrobial drugs, interpretative rules in breakpoints in Europe, both for therapy susceptibility testing and anaerobe and for antimicrobial resistance surveil- bacteria are operative. lance, as well as a lack of a uniform 6. A European disk test for routine European processes for setting break- susceptibility testing is being developed. points for new antimicrobial agents. Potential applications: AIMS Europe is in need of uniform breakpoints The main objective was to provide Europe for the categorisation of bacteria and fungi with harmonised antimicrobial breakpoints in susceptible, intermediate and resistant for existing drugs and a pathway through categories for therapy with antimicro- which new drugs can receive uniform bial drugs and for the measurement of breakpoints in Europe. The EUCAST antimicrobial resistance development. consortium also sought to cooperate with all expert groups and European agencies with an interest in antimicrobial breakpoints, and to set up a website for the dissemination of key materials.

 Project number: 2003210  EC contribution: € 355.680,00  Duration: 36 months  Type: Public Health Action – Health Threats – Health Action Programme 2003  Starting date: 1 May 2004 50 | EUCAST

Project Coordinator Gunnar Kahlmeter Chairman of EUCAST (2002 – 2008) Clinical Microbiology Central Hospital 351 85 Växjö, Sweden E-mail: [email protected] Partners Dr. Derek Brown British Society for Antimicrobial Chemotherapy (BSAC), United Kingdom Prof. Claude-James Soussy Comité de l’antibiogramme de la Société Française de Microbiologie (CA-SFM), France Dr. Arne Rodloff Deutsche Industrie Norm-Medizinische Mikrobiologie (DIN), Germany Dr. Johan W Mouton Commissie Richtlijnen Gevoeligheidsbepalingen (CRG), Netherlands Dr. Inga Odenholt Swedish Reference Group for Antibiotics (SRGA), Sweden Dr. Martin Steinbakk Norwegian Working Group on Antibiotics (NWGA), Norway EUR-INTAFAR | 51

Inhibition of new targets for fighting antibiotic resistance http://www.eur-intafar.eu

BACKGROUND transpeptidases that are resistant Peptidoglycan (PG) biosynthesis and to most clinically useful β -lactams. bacterial cell morphogenesis are related Various novel methods have been phenomena and are totally specific to devised to test inhibitors prepared by bacterial cells without even remotely the chemist partners. equivalent systems in eukaryotic cells. The The partners have shown that lactivicin, enzymes and proteins involved in these the only known natural compound processes are thus promising targets for exhibiting such properties, is active the design of new antibiotics. Interfer- against clinically isolated penicillin- ing with the activities of the participat- resistant S. pneumoniae strains. ing enzymes or with the protein-protein Crystallographic studies performed interactions that take place along these with S. pneumoniae PBP 1b reveal metabolic pathways should perturb the that the inactivation reaction involves bacterial cell cycle and, hopefully, supply opening of both cycloserine and new weapons to fight dangerous patho- -lactone rings of lactivicin. Thus, genic organisms such as the methicillin- lactivicin derivatives will be useful resistant Staphylococcus aureus (MRSA). in the search for antibiotics active against β -lactam resistant bacteria. Problem: 2. Screening forinhibitors of The increase in antibiotic resistance is glycosyltransferase (GTase) activity a global problem, both for nosocomial yielded 30 potential inhibitors among and community-acquired infections. which two were found to inhibit GTAse activity of E.coli PBP 1b. AIMS 3. The steps preceding transglycosylation The aim of the EUR-INTAFAR network is to and transpeptidation result in an find new targets for antibiotics and to use outward-oriented lipid II. They involve the knowledge amassed on the antibiotic- the synthesis of lipid II by MraY and resistant forms of the ‘old’ targets for MurG followed by translocation of the the design of more efficient molecules. disaccharide-peptide moiety across the cytoplasmic membrane. The synthesis OBTAINED RESULTS and translocation have been studied. 1. Transpeptidases (Tpases) or Penicillin- 4. Only two clinically useful antibiotics Binding-Proteins (PBPs) are the targets are presently available which target of β -lactamantibiotics. However, the intracellular steps leading to the some pathogenic bacteria such as soluble PG precursors and one of them Streptococcus pneumoniae and the (cycloserine) might be withdrawn in methicillin-resistant Staphylococcus the near future. All the intermediate aureus MRSA have acquired metabolites have been prepared and a

 Project number: LSHM-CT-2004-512138  EC contribution: €11 301 842  Duration: 60 months  Type: Integrated Project  Starting date: 1 January 2005 52 | EUR-INTAFAR

novel class of MurD inhibitors has been Dr. Didier Blanot identified. The structure of an enzyme Université de Paris-Sud Orsay, France inhibitor complex has been solved. 5. In S. pneumoniae, new enzymes Dr Eefjan Breukink Utrecht University participating in teichoic acid Utrecht, Netherlands biosynthesis have been identified Dr. Andréa DessenInstitut de Biologie and the long-standing problem Structurale Jean-Pierre Ebel about why S. pneumoniae requires Grenoble, France choline for growth was solved. Dr. Waldemar Vollmer 6. An innovative high-throughput system Universität Tübingen Tübingen, Germany has been developed for screening chemical compound libraries in Prof Regine Hakenbeck University of Kaiserslautern microspots (EU patent application Kaiserslautern, Germany submitted, February 2008). Dr. Michel Arthur Université Paris VI Potential applications: Paris, France This project is of prime importance as a Prof. Ian Chopra springboard to re-activate the important University of Leeds Leeds, England, UK therapeutic area of antibiotic drugs. A better understanding of the physiology and bi- Dr. Jean-Pierre Simorre Institut de Biologie Structurale ochemistry of bacterial cell morphogenesis Grenoble, France and peptidoglycan biosynthesis will create Dr. André Luxen new avenues for the design and synthesis University of Liège of efficient antimicrobials. This will make Liège, Belgium new opportunities available for companies Prof. Christopher Schofield of different sizes to develop these com- Oxford University Oxford, England, UK pounds until they reach the clinical level. Prof. Yves Le Merrer Université René Descartes Project Co-Coordinator Paris, France Prof. Jean-Marie Frère Centre for Protein Engineering Dr. Stanislav Grobec Institut de Chimie B6a University of Ljubljana University of Liège Ljubljana, Slovenia Sart-Tilman B400 Liège, Belgium Prof. Uros Urleb Lek Pharmaceuticals d.d. Tel 32 4 366 33 98 Ljubljana, Slovenia Fax 32 4 366 33 64 Email:[email protected] Dr. Frédéric Marc ProtNeteomix SAS Partners Nantes, France Dr. Tanneke Den Blaauwen Dr. Waldemar Vollmer University of Amsterdam University of Newcastle upon Tyne Amsterdam, Netherlands Newcastle upon Tyne, England, UK EURESFUN | 53 Integrated post-genomic approaches for the understanding, detection and prevention of antifungal drug resistance in fungal pathogens http://www.chuv.ch/imul/euresfun

BACKGROUND arrays for drug target genes for The EURESFUN (EUropean RESistance drug discovery by a small and FUNgal) network used genomics-based medium-sized enterprise (SME); integrated approaches to study antifungal establishing data on resistance resistance in relevant fungal pathogens incidence and prevalence, and linking (Candida, Aspergillus). Using microarray clinical data on susceptibility to known strategies and systematic deletion/over-ex- antifungals with a therapy outcome. pression approaches, the network sought to unravel potential novel targets for antifun- EXPECTED gal drug discovery, but also to yield diag- AND OBTAINED RESULTS nostic tools and mutations suitable for use EURESFUN anticipated the fol- in resistance monitoring and surveillance. lowing results:

Problem: identification of specific mutations The frequency of fungal infections has been linked to antifungal resistance; steadily increasing in the human popula- identification of cellular components tion worldwide over the past decades. and isolation of their inhibitors; Several fungal pathogens cause severe collection of strains displaying a fungal infections in hospitals. Among wide range of susceptibility to known them, the most important are Candida antifungals and associated with albicans, C. glabrata and Aspergillus molecular epidemiology data; fumigatus. C. albicans accounts for more generation of novel diagnostic tools en- than 50% of all fungal infections, caus- abling genotyping, species identification ing both superficial and disseminated and antifungal resistance monitoring. infections, while C. glabrata infections account for 10 - 20% of the cases. Potential applications: The diagnostic tools would rapidly detect The exposure of fungal pathogens to anti- mechanisms of resistance, impact on the fungal agents has different outcomes, one costs associated with the treatment of of which is the development of resistance. fungal infections and reduce the social burden of these infections. The European AIMS industry’s competitiveness in the field The aims of EURESFUN included: of diagnostics would be reinforced.

designing new therapeutic strategies to improve the efficacy of existing antifungal therapy; establishing and using cell-based

 Project number: LSHM-CT-2005-518199  EC contribution: €2 755 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 November 2005 54 | EURESFUN

Project Coordinator Prof. Dominique Sanglard Centre Hospitalier Universitaire Vaudois Institut de Microbiologie Rue du Bugnon 48 1011 Lausanne, Switzerland Tel. +41 213144083 Fax +41 213144060 E-mail: [email protected]

Partners Dr Christophe d’Enfert Institut Pasteur Paris, France Prof. Karl Kuchler Medizinische Universität Wien Vienna, Austria Prof. Uwe Gross Georg-August Universitaet Goettingen Göttingen, Germany Dr Steffen Rupp Fraunhofer Gesellschaft Stuttgart, Germany Prof. Steven Kelly University of Wales Swansea Swansea, Wales, UK Dr Emilia Mellado Istituto de Salud Carlos III Madrid, Spain Prof. Frank Odds The University Court of the University of Aberdeen Aberdeen, Scotland, UK Dr Johannes Regenbogen GATC Biotech AG, R&D Konstanz, Germany Dr Derek Law F2G Ltd Manchester, England, UK EuResist | 55 Integration of viral genomics with clinical data to predict response to anti-HIV treatment http://www.euresist.org

BACKGROUND EXPECTED RESULTS The EuResist project has developed a The EuResist Integrated Data- European integrated system for clini- base has been realised by physi- cal management of antiretroviral drug cally merging the founding ARCA, resistance. The system will provide Arevir and Karolinska databases. the clinicians with an online prediction of response to antiretroviral treatment A Standard Datum has been defined in HIV patients, thus helping the clini- in compliance with the definition pro- cians choose the best drug combina- posed by the Forum for Collaborative tions for any given HIV genetic variant. HIV Research (www.hivforum.org).

Problem: Different predictive methods have been While combination antiretroviral therapy developed and compared. Three en- has made HIV infection a treatable gines have been chosen as the best condition, eradication of infection is not performers: Generative-Discriminative yet achievable and antiretroviral therapy (GD), Evolutionary (EV) and Higher order needs to be administered as a prolonged, interaction, or Mixed Effects (ME). possibly lifelong treatment. Long-term toxicity, difficulty in adhering to complex The EuResist Web interface has regimens, possible pharmacokinetics been developed under the guid- problems, and intrinsically limited potency ance of virologists and physicians. are all factors favouring the selection of drug-resistant viral strains. Develop- Potential applications: ment of drug resistance is nowadays The project can be considered as a a major cause for treatment failure. pilot for Hepatitis C virus (HCV) and Hepatitis B virus (HBV) since a large AIMS antiviral treatment intervention has been The EuResist objectives included: started and the chronic nature of both of these viruses is expected to lead to integration of biomedical informa- the development of drug resistance. tion from three large and expanding European databases; combination and availability of the best performing models into the final EuResist Combined Predictive System.

 Project number: IST-2004-027173  EC contribution: €2 143 000  Duration: 30 months  Type: Specific Targeted Research Project  Starting date: 1 January 2006 56 | EuResist

Project Coordinator Partners Dr Francesca Incardona Dr Anders Sönnerborg Informa Srl Karolinska Institutet via dei Magazzini Generali 13 Karolinska University Hospital 00184 Rome, Italy Stockholm, Sweden Tel. +39 065758926 Fax +39 065759937 Dr Rolf Kaiser E-mail: [email protected] Universitaetsklinikum Köln Institute of Virology Scientific Coordinator Cologne, Germany Prof. Maurizio Zazzi Dr Shai Fine Università degli Studi di Siena IBM Israel – Science and Technology Ltd Department of Molecular Biology – Haifa, Israel Section of Virology Prof. Thomas Lengauer V lotto, piano 2 Policlinico Le Scotte Max-Planck Gesellshaft zur Foerderung Viale Bracci der Wissenshaften e.v. 53100 Siena, Italy Computational Biology and Applied Algorithmics Tel. +39 0577233850 Saarbrücken, Germany Fax +39 0577233870 E-mail: [email protected] Dr Fulop Bazso MTA KFKI Reszecske-ES Magfizikai KutatoIntezet Department of Biophysics Budapest, Hungary Dr Andrea Petroczi Kingston University Kingston upon Thames, England, UK Eurofungbase | 57 Strategy to build up and maintain an integrated sustainable European fungal genomic database required for innovative genomics research on filamentous fungi important for biotechnology and human health http://www.eurofung.net

BACKGROUND AIMS Eurofungbase targeted the creation of The aim was to develop a strategy to build conditions and facilities within Europe up and maintain an integrated, sustainable to widely apply all genomics technolo- European genomic database required for gies in filamentous fungal research. This innovative genomics research of filamen- is expected to expand knowledge and tous fungal model organisms of interest. benefit Europe’s biotechnology indus- This database will become a crystallisa- tries, as well as help improve the prevention point for related systems and could tion and treatment of fungal disease. then be integrated and conserved in a central European genomic database. The project focused on several filamentous fungi for different reasons; one was EXPECTED RESULTS Aspergillus nidulans for its long record Eurofungbase anticipated several results: of use as a fungal model organism. contribution of the community The human pathogen Aspergillus fumiga- to the manual annotation of im- tus serves not only as a model pathogen, portant fungal genomes through but becomes more and more a seri- annotation jamborees; ous threat to human health. The project realisation of an integrated sustain- contributes to create the conditions and able fungal genomic database; facilities within Europe to widely apply realisation of a fungal genom- all genomics technologies in filamentous ics knowledge base for the Eu- fungal research. This will greatly expand rofungbase community and the our knowledge about filamentous fungi. European fungal biotech industry; This new genomics information will thus intensified collaboration between be beneficial to Europe’s biotechnology the members of the network; industries and help to improve the preven- individualised training of a next generation and treatment of fungal disease. tion of young scientists in fungal genomics and biotechnological research. Problem: Widespread genomic research leads Potential applications: to enormous amounts of data stored in Fungi play an important role in White many small databases across Europe. For Biotechnology (e.g. biomass saccha- integrated European genomic research, rification, biorefinery). The results of this it is important that such data become project will find their way in new experi- easily accessible for all researchers. mental approaches in those areas.

 Project number: LSSG-CT-2005-018964  EC contribution: €485 874  Duration: 36 months  Type: Coordinated Action  Starting date: 1 November 2005 58 | Eurofungbase

Project Coordinator Prof. Cees A.M.J.J. van den Hondel Leiden Universiteit Institute Biology Leiden Wassenaarseweg 64 2333 AL Leiden, Netherlands Tel. +31 0715274938 E-mail: [email protected]

Partners For the full list of participants and a list of members of the Fungal Industrial Platform, see http://eurofung.net/index. php?option=com_content&task=blogcategor y&id=13&Itemid=14 and http://eurofung.net/index.php?option=com_ content&task=blogcategory&id=12&Itemi d=15 online. Prof. Steve Oliver University of Manchester Manchester, England, UK Prof. Dave Ussery Technical University of Denmark Lyngby, Denmark EPG | 59 European virtual institute for functional genomics of bacterial pathogens – EuroPathoGenomics http://www.noe-epg.uni-wuerzburg.de

BACKGROUND consortium will analyse the mechanisms The study of infectious disease, which conferring to the development and spread is established in Europe in the form of of antibiotic resistances among bacteria. various national research centres and a considerable number of laboratories, EPG will establish a higher standard in the needs a multidisciplinary approach that infectious diseases teaching field. Thus, a brings together the different disciplines of permanent and durable structure will be molecular biology, immunology, cell biology created that will maximise the contribu- and structural biology. The Network of tions of European scientists to this area. Excellence is forging permanent links and structures between the different disciplines. Potential applications: EPG will promote discoveries leading to Problem: the development of innovative diagnostic There is an urgent need for research in the tools, the discovery of novel anti-infectious field of infectious diseases. Many pathogens agents and their targets, the identifica- become increasingly resistant to available tion of new antigens and the decipher- drugs and antibiotics. The prevalence of anti- ing of host defence mechanisms. biotic resistances is increasing in both devel- Project Coordinator oped and developing countries. They impose Prof. Dr Jörg Hacker an important socioeconomic burden on the Bayerische Julius-Maximilians-Universität public, industry and the healthcare system. Würzburg Institut für Molekulare Infektionsbiologie Röntgenring 11 AIMS 97070 Würzburg, Germany EPG seeks to stimulate multidisciplinary Tel. +49 931312575 Fax +49 931312578 collaborative research activities, create E-mail: [email protected] a European training facility for teaching of scientists and physicians, and foster Partners biotechnological applications and technol- Prof. Dr Jürgen Wehland Helmholtz-Zentrum für Infektionsforschung ogy transfer to European companies. Braunschweig, Germany Prof. Dr Thomas F. Meyer EXPECTED RESULTS Max-Planck-Institut für Infektionsbiologie The expected deliverables are innovations Berlin, Germany in the areas of diagnostics, drug and vac- Dr Carmen Buchrieser cine development. The project will promote Institut Pasteur discoveries leading to the development of Paris, France innovative diagnostic tools, the identifica- Dr Jean-Michel Claverie tion of new antigens and the decipher- Centre National de la Recherche Scientifique (CNRS) ing of host defence mechanisms. The Marseille, France

 Project number: LSHB-CT-2005-512061  EC contribution: €6 700 000  Duration: 60 months  Type: Network of Excellence  Starting date: 1 July 2005 60 | EuropeHIVResistance

European cohort coordinating network on HIV drug resistance

http://www.europehivresistance.org

BACKGROUND of HIV, as well as for the prevention of EuropeHIVResistance will create and drug-resistant HIV variants transmission. maintain a pan-European cohort with a network of virological reference cen- Project Coordinator tres in over 30 European countries. Prof. Dr Charles Boucher University Medical Center Utrecht Department of Virology, GO4.614 Problem: Heidelberglaan, 100 HIV resistance to one or more antiretro- NL-3584 CX Utrecht Tel: +31-88-7556526 viral drugs is spreading throughout the Fax: 31-30-7555426 world. Of major concern is the possibility Email: [email protected] that no effective antiretroviral drugs will be available for newly infected patients. Partners Dr Jan Albert AIMS Swedish Institute for Infectious Diseases Control Solna, Sweden The aim of EuropeHIVResistance is to create a large pan-European cohort for studying Dr Claus Nielsen Statens Serum Institut Copenhagen the appearance, spread, virological deter- Copenhagen, Denmark minants and clinical consequences of HIV Prof. Anne-Mieke Vandamme resistance under joint standards linked to a Katholieke Universiteit Leuven common shared self-sustainable database. Leuven, Belgium Prof. Claudia Balotta EXPECTED RESULTS University of Milan Milan, Italy The EuropeHIVResistance network will make a major contribution in the following Dr Jean-Claude Schmit Centre de Recherche Public - Santé ways: by (i) expanding HIV-drug resist- Luxembourg, Luxembourg ance surveillance and follow-up activities Dr Angelos Hatzakis to a pan-European level; (ii) decreasing the Hellenic Scientific Society for the Study of AIDS fragmentation of HIV resistance research in and Sexually Transmitted Diseases Athens, Greece central and eastern Europe; (iii) increasing the level of virological expertise and skills in Dr Ricardo Camacho Universidade Nova de Lisboa HIV resistance in this region; and (iv) secur- Lisbon, Portugal ing the desired exchange of good practices Dr Birgitta Äsjö between the HIV/AIDS cohorts in Europe National Institute of Public Health and the World Health Organization (WHO). Oslo, Norway Dr Elisabeth Puchhammer-Stöckl Potential applications: Medical University of Vienna This network will help develop better Vienna, Austria guidelines for the treatment and prevention

 Project number: LSHP-CT-2006-518211  EC contribution: €1 499 336  Duration: 48 months  Type: Coordinated Action  Starting date: 1 March 2006 EuropeHIVResistance | 61

Dr Mika Salminen Dr Olga Kravchenko National Public Health Institute Ukrainian AIDS Center Helsinki, Finland Kiev, Ukraine

Dr Klaus Korn Dr Suzie Coughlan University of Erlangen-Nurnberg University College Dublin Erlangen, Germany Dublin 4, Ireland

Dr Andrzej Horban Dr Deenan Pillay Hospital for Infectious Diseases Royal Free Hospital and University College Warsaw, Poland Medical School Dr Bonaventura Clotet London, England, UK Fundacio IrsiCaixa Dr Marie Bruckova Badalona (Barcelona), Spain National Institute of Public Health Dr Danail Beshkov Prague, Czech Republic National Center of Infectious and Parasitic Diseases Dr Kai Zilmer Sofia, Bulgaria West-Tallinn Central Hospital Tallinn, Estonia Dr Leondios Kostrikis University of Cyprus Dr Maja Stanojevic Nicosia, Cyprus University of Belgrade School of Medicine Belgrade, Serbia Dr Janos Minarovits National Public Health Dr Danica Stanekova and Medical Officer Service Slovak Medical University Budapest, Hungary Bratislava, Slovakia

Prof. Baiba Rozentale Dr Zehava Grossman Infectology Center of Latvia Public Health Laboratories, Ministry of Health Riga, Latvia Jerusalem, Israel

Dr Algirdas Griskevicius Prof. Victor Marievskiy Lithuanian AIDS Center Institute of Epidemiology and Infectious Diseases Vilnius, Lithuania Kiev, Ukraine Prof. Adrian Streinu Cercel Dr Sabine Yerly and Prof. Matei Bals Hospital Cantonal Universitaire Genève Institute for Infectious Diseases Geneva, Switzerland Bucharest, Hungary Prof. Mario Poljak SMEs University of Ljubljana Slovenian AIDS Reference Centre Ms Alice Posthumus-Plantinga Ljubljana, Slovenia Virology Education Utrecht, Netherlands Prof. Francoise Brun-Vezinet Bichat Claude Bernard University Hospital Dr Shalom Sayada Paris, France Advanced Biological Laboratories SA Luxembourg, Luxembourg Prof. Vadim Pokrovsky Federal State Institution Central Research Dr Paul Wallace Institute of Epidemiology Quality Control for Molecular Diagnostics Moscow, Russia Glasgow, Scotland, UK 62 | EuroTB

Surveillance of tuberculosis in Europe

http://www.eurotb.org

BACKGROUND EXPECTED EuroTB was established in 1996 to improve AND OBTAINED RESULTS the contribution of epidemiological surveil- The results of EuroTB activities are lance to tuberculosis (TB) control in Europe. documented in the following manner: The project coordinated the surveillance of TB in the 53 countries of the World 1. yearly reports: ‘Surveillance of Health Organization’s (WHO) European tuberculosis in Europe’; Region through contact points based in the 2. European TB data sets: case- national TB surveillance institutions that re- based (1) and aggregated (6); port standardised data annually to EuroTB. 3. MDR-TB: reports and a genotype website; Problem: 4. final report on molecular surveillance TB is a directly communicable condition of MDR-TB (end-2007); and transmission most often occurs follow- 5. scientific papers and communications; ing the inhalation of droplets from a person 6. ad hoc reports on expert with active TB. It is a serious disease which consultations following country can lead to death, disability and chronicity. visits to enhance surveillance; 7. quarterly EuroTB newsletter. AIMS The mission statement of EuroTB: ‘To Potential applications: improve the contribution of surveil- 1. Formulation of policy relating lance to TB control in Europe’. to TB and MDR-TB. 2. Scientific pursuit. The general objectives of 3. Use for preparation of reports, lectures, the project included: and presentations by experts. 4. Information for awareness campaigning. coordinating and enhancing surveillance of TB in Europe; Project Coordinator monitoring and comparing trends Dr Dennis Falzon in TB morbidity in Europe and char- Institut de Veille Sanitaire 12, rue du Val d’Osne acterising vulnerable populations; 94415 Saint-Maurice, France contributing to the harmonisation of Tel: 00 33 1 41 79 68 04 Fax: 00 33 1 41 79 68 02 the investigation of TB contacts and E-mail: [email protected] the management of TB outbreaks at the national and EU levels.

 Project number: 2004213  EC contribution: €773 510  Duration: 36 months  Type: Health project  Starting date: 1 January 2005 EuroTB | 63

Partners Dr Vincent Kuyvenhoven Dr. Kristin Kremer and Dr. Herre Heersma KNCV Tuberculosis Foundation National Institute of Public Health The Hague, Netherlands and the Environment Dr Maria Korzeniewska-Kosela Bilthoven, Netherlands National TB and Lung Diseases Institute Warsaw, Poland Other partners Dr. Elmira Ibraim (not contributing to the budget) Institute of Pneumology Marius Nasta Bucharest, Romania Dr Andrea Ammon European Centre for Disease Prevention Prof. Francis Drobniewski and Control Institute of Cell and Molecular Sciences Stockholm, Sweden London, England, UK Dr. Mehran Hosseini Dr John Watson HIV/AIDS, Tuberculosis & Malaria, WHO Health Protection Agency Geneva, Switzerland London, England, UK Dr. Abigail Wright Stop TB Department, WHO Geneva, Switzerland Dr Richard Zaleskis WHO Regional Office for Europe Copenhagen, Denmark EuroTB Advisory Committee Members Dr Jean-Paul Klein Bundesministerium fuer Gesundheit und Frauen Vienna, Austria Dr Richard Zaleskis WHO Regional Office for Europe Copenhagen, Denmark Dr Petri Ruutu KTL Helsinki, Finland Dr Michael Forssbohm Landeshauptstadt Wiesbaden, Gesundheitsamt, Abteilung fuer Infektionsschutz, Wiesbaden, Germany Prof. Luke Clancy International Union Against Tuberculosis & Lung Disease (UNION) – European region Newcastle (Co. Dublin), Ireland 64 | FUNGWALL

The fungal cell wall as a target for antifungal therapies

BACKGROUND OBTAINED RESULTS Fungal pathogens represent the major The achievements of the project have eukaryotic agents of serious infection in placed Europe in a world-leading posi- European countries. Infections due to tion for analysis of fungal cell wall. The Candida albicans and Aspergillus fumiga- coupling of biochemical and genetic tus are the most common and clinically methodologies was extremely syner- important pathogens and were therefore getic for tackling this problem and has the focus of this project. There is an urgent given a unique flavour to FUNGWALL. need to generate new, efficacious, non- toxic compounds with broad-spectrum The 36-month FUNGWALL project led antifungal activity. The challenge for to many achievements, including: FUNGWALL was to investigate mechanisms of fungal cell wall synthesis in order validation of chitin synthesis to identify new antifungal targets to control as a legitimate target for an- human fungal infections in Europe. tifungal chemotherapy; elucidation of the mode of ac- AIMS tion of aminocandin through vari- The cell wall of pathogenic fungi is a good ous genomic strategies; target for the development of new drugs development of methodologies to ana- for the following reasons: (1) The fungal lyse carbohydrate-protein interactions; cell wall is required for fungal cell integrity and is essential for fungal growth and for Thus, several new drug targets were identi- virulence; (2) Polysaccharidic components fied during the course of FUNGWALL: of the cell wall are unique to fungi and consequently, putative inhibitors of the chitinases and endo β1,3 glucanases; biosynthetic pathways responsible for cell new transglycosidases re- wall construction can be potent antifungals. modelling β glucans; O-mannosyltransferases. The objectives of FUNGWALL centred on the assembly of the cell wall polysaccharide Project Coordinator skeleton. The project partners focused on Prof. Jean-Paul Latge the identification of new-generation antifun- Unité des Aspergillus Institut Pasteur gals that target fungal cell wall biosynthesis. 75724 Paris, France Tel. +33 01406135 19 E-mail: [email protected]

 Project number: LSHB-CT-2004-511952  EC contribution: €2 895 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2005 FUNGWALL | 65

Partners Prof. Neil A. R. Gow School of Medical Sciences Aberdeen, Scotland, UK Dr Frans M. Klis Swammerdam Institute for Life Sciences Amsterdam, Netherlands Prof. Jean-Marie François UMR CNRS 5504 & INRA 792 Toulouse, France Dr Bernard Henrissat CNRS, Universités Aix-Marseille I & II Marseille, France Dr Carlos R. Vazquez de Aldana CSIC-Universidad de Salamanca Salamanca, Spain Prof. Dr Sabine Strahl Ruprecht-Karls-Universität Heidelberg Heidelberg, Germany Dr Javier Arroyo Universidad Computense de Madrid Madrid, Spain Dr Daan van Aalten University of Dundee Dundee, Scotland, UK Dr Michael T. Black Novexel - Parc Biocitech Romainville, France 66 | GENOSEPT Genetics of sepsis in Europe

http://www.genosept.eu

BACKGROUND Potential applications: GenOSept used a multidisciplinary funda- The GenOSept findings will con- mental genomics approach (gene expres- tribute to reducing sepsis mortality sion, structural genomics and population and morbidity in European ICUs. genetics) to examine genetic predisposition to sepsis. The partners aimed to stand- Project Co-Coordinators ardise protocols for genotyping, facilitate Prof. Julian Bion and Dr Nathalie Mathy application of new knowledge in func- European Society of Intensive Care Medicine Brussels, Belgium tional and structural genomics, harmonise Tel. 32 2 5590353 high-throughput genotyping and quality Fax 32 25270062 E-mail: [email protected] control between major European centres, and contribute to reducing sepsis-related Partners mortality in European healthcare. Prof. Dr Frank Stüber Rheinische Friedrich-Wilhelms-Universität Bonn Bonn, Germany AIMS Prof. Jean-Daniel Chiche The major milestones of GenOSept were: INSERM Paris, France

consensus definitions and the set- Prof. Adrian Hill University of Oxford ting up of an inclusion and ex- Oxford, England, UK clusion criteria database; Prof. Vito Marco Ranieri collection of blood samples from Universita degli Studi di Torino Turin, Italy about 2 500 patients all over Europe; Prof. Jordi Rello blood genotyping and genetic testing; University Rovira & Virgili – Hospital Universitari identification of relevant candidate Joan XXIII genes and their genomic variations; Tarragona, Spain genetic epidemiology study to Prof. Thomas Meitinger Helmholtz Zentrum München be performed in European in- Neuherberg, Germany tensive care units (ICUs); Dr Yoram Weiss definition of a diagnostic Single- Hadassah Medical Organisation Jerusalem, Israel Nucleotide Polymorphism (SNP) set. Prof. Dr Stefan Russwurm SIRS-Lab GmbH EXPECTED Jena, Germany AND OBTAINED RESULTS Prof. Marion Schneider The expected results of GenOSept University Ulm Medical Faculty Ulm, Germany are that, among others, it will: Prof. Konrad Reinhart Klinikum der Friedrich-Schiller-Universität Jena contribute to unravelling the ge- Jena, Germany netic predisposition of sepsis; Dr Vladimir Sramek Masaryk University Brno Medical Faculty define novel candidate genes Brno, Czech Republic by gene expression studies; Dr Ilona Bobek include genes directing pathways National Medical Center of the host immune response to Budapest, Hungary infection and inflammation, and Dr Silver Sarapuu Tartu University Clinics of programmed cell death. Tartu, Estonia

 Project number: LSHB-CT-2004-512155  EC contribution: €2 000 000  Duration: 48 months  Type: Specific Targeted Research Project  Starting date: 1 January 2005 GRACE | 67 Genomics to combat resistance against antibiotics in community-acquired LRTI in Europe http://www.grace-lrti.org

BACKGROUND wide infrastructure to investigate and GRACE is a Network of Excellence focus- improve the management of CA-LRTIs. ing on the complex and controversial field of community-acquired lower respiratory EXPECTED tract infections (CA-LRTIs). The promis- AND OBTAINED RESULTS cuous use of antibiotics to treat LRTIs Delivery of an Internet Web portal accounts for a major part of the community under a common corporate iden- burden of antibiotic use and contributes tity integrating all IT functions. dramatically to the rising prevalence of Development of a platform, GOS resistance among major human patho- (GRACE Online System), serving gens. GRACE will combat antimicrobial internal purposes and dissemina- resistance through integrating centres of tion of results to the public. research excellence and exploit genom- Establishment of a microbial diagnos- ics in the investigation of CA-LRTIs. tic network of laboratories to develop novel rapid genome-based diagnostic Problem: tests for the detection of pathogens. CA-LRTIs are the leading reason for Identification of susceptibility genes seeking medical care. Yet there are by using candidate genes as well as a few conditions in medicine that are so genome-wide association approach in controversial. These uncertainties have more severe LRTIs, such as invasive resulted in prescriptive promiscuity, which pneumococcal disease cases. As a largely explains the escalating antibiotic result of candidate gene studies, the resistance of common bacterial respira- list of known susceptibility genes has tory pathogens in the community. There been extended to eight in total (i.e. are no good studies of sufficient size on MBL, CD32, CRP, PTPN22, TLR1-6-10, detecting bacterial aetiology of LRTIs and MAL/TIRAP, NFKBIA, and NFKBIE). on diagnosis of Community-acquired Detection and analyses of new viruses pneumonia (CAP) in primary care. to contribute to our understanding of the mechanisms of LRTIs, and AIMS development of methods that may be GRACE aims to strengthen European applicable for analysis of the etiol- human and microbial genomic research ogy of other infectious diseases. excellence, focusing on CA-LRTIs, which Establishment and evaluation of is the leading reason for seeking medi- the molecular methods that will cal care and consuming antibiotics. The be used using an existing collec- hallmark of the Network of Excellence tion of pneumococcal isolates. created by GRACE will be the integration Variability in both prescription and of research platforms creating a European- antibiotic choice across Europe.

 Project number: LSHM-CT-2005-518226  EC contribution: €11 500 000  Duration: 60 months  Type: Network of Excellence  Starting date: 1 March 2006 68 | GRACE

Project Coordinator Prof. Hermínia de Lencastre Prof. Herman Goossens Instituto de Tecnologia Química e Biológica Oeiras, Portugal University of Antwerp Department of Medical Microbiology Dr. José Campos Universiteitsplein 1 S3 Instituto de Salud Carlos III B-2610 Wilrijk-Antwerp, Belgium Majadahonda, Spain Tel. +32 38213789 Prof. Joanna Coast Fax +32 38254281 University of Birmingham E-mail: [email protected] Birmingham, England, UK Manager Prof. Lia van der Hoek University of Amsterdam Dr. Katherine Loens Amsterdam, Netherlands University of Antwerp Department of Medical Microbiology Dr. Richard Smith Universiteitsplein 1 S009a London School of Hygiene & Tropical Medicine B-2610 Wilrijk-Antwerp, Belgium London, England, UK Tel. +32 38202418 Dr. Bernadett Kovacks Fax +32 38202752 Drug Research Centre Ltd E-mail: [email protected] Balatonfüred, Hungary Partners Dr. Antoni Torres Clinical Thorax Institute Prof. Greet Ieven Barcelona, Spain Universiteit Antwerpen - Campus Drie Eiken Wilrijk, Belgium Dr. Zuzana Bielicka Clinical Research Associates and Consultants Dr. Alexander Gorbalenya Bratislava, Slovakia Leids Universitair Medisch Centrum Leiden, Netherlands Dr. Maciek Godycki-Cwirko Medical University of Lodz Dr. Derrick Crook Lodz, Poland University of Oxford Oxford, England, UK Dr. Jordy Almirall Hospital of Mataro Prof. David Holden Mataro, Spain Imperial College London London, England, UK Dr. Tom Schaberg Diakoniekrankenhaus Dr. Birgitta Henriques Normark Rotenburg, Germany Smittskyddsinstitutet Solna, Sweden Dr. Sigvard Mölstad Linköpings Universitet Prof. Christopher C. Butler Jönköping, Sweden University of Wales College of Medicine Cardiff, Wales, UK SMEs: Prof. Theo Verheij, Robert Veen, Guido Krupp Dr Anton M. van Loon AmpTec GmbH Universitair Medisch Centrum Utrecht Hamburg, Germany Utrecht, Netherlands Jan Schouten Dr. Paul Little MRC-Holland University of Southampton Amsterdam, Netherlands Southampton, England, UK Guus Simons Prof. Roger Finch PathoFinder University of Nottingham Maastricht, Netherlands Nottingham, England, UK Thierry Leclipteux Prof. Francesco Blasi Coris BioConcept Universita degli Studi di Milano Gembloux, Belgium Milan, Italy Dr. Peter Garred Scientific societies: Tissue Typing Laboratory - Section 7631 Copenhagen, Denmark Javier Garau European Society for Clinical Microbiology Prof. Staffan Normark and Infectious Diseases (ESCMID) Karolinska Institutet University of Barcelona Solna, Sweden Terrassa, Spain Prof. Regine Hakenbeck Séverin Tania Universität Kaiserslautern European Respiratory Society (ERS) Kaiserslautern, Germany Lausanne, Switzerland HAPPY AUDIT | 69 Health alliance for prudent prescribing, yield and use of antimicrobial drugs in the treatment of respiratory tract infections http://www.happyaudit.org/

BACKGROUND Potential applications: The HAPPY AUDIT project aims to The project will show examples on best strengthen the surveillance of respiratory practice and how GPs will benefit from tract infections (RTIs) in primary healthcare intervention activities. They will under- in Europe through the development of line the message that there are barriers intervention programmes targeting general to overcome, but that the changing of practitioners (GPs), parents of young chil- behaviour towards prudent use of antibiot- dren and healthy adults. The intervention ics will lead to a healthier society. In this programme will curb the occurrence of way the intervention will create goodwill, bacterial resistance by reducing the pre- understanding and backing for the public. scription of unnecessary antibiotics for RTIs and by improving the use of appropriate The HAPPY AUDIT is using a bottom-up antibiotics in suspected bacterial infections. approach in the trial to change behaviour among professionals. Patients may act Problem: as professionals if their knowledge about Infections caused by resistant bacteria their diseases is relevant and rational. lead to increased mortality, prolonged Especially for young people, familiar with hospital stays and increased costs. the modern electronic communication messages, there will be a tendency to AIMS discuss with doctors and nurses about HAPPY AUDIT aims to change peo- new therapies as well as question old ones. ple’s habits towards the prudent use of antimicrobial agents (antibiotics) Project Coordinator via the Audit Project Odense (APO) Dr Lars Bjerrum method, developed and successfully Research Unit for General Practice J.B. Winsløws Vej 9A tested by GPs in the Nordic countries. 5000 Odense C, Denmark Tel. +45 65503091 Fax +45 65503980 EXPECTED RESULTS E-mail: [email protected] The HAPPY AUDIT results will be available at local and European level, and in the education sector, ensuring that the message has a deep impact on the younger generation. The intervention will have strong visual potential that will make it ap- pealing to people at all levels. The ambition is to create a differentiated teaching material that is suited for different age groups.

 Project number: SP5A-CT-2007-44154  EC contribution: €1 492 300  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 April 2007 70 | HAPPY AUDIT

Partners Dr Anders BjerrumGeneral Practice Consultants Odense C, Denmark Dr Jens Peter Kampmann Ministry for the Interior and Health Copenhagen, Denmark Dr Ingvar Ovhed Lund University Malmö University Hospital Malmö, Sweden Dr Ingrid Schmidt National Board of Health and Welfare Stockholm, Sweden Dr Ruta Radzeviviene Mano seimos gydytojas (My family doctor) Klaipeda, Lithuania Dr Ausra Pikelyte Valstybine ligoniu kasa (State Patient Fund) Klaipeda, Lithuania Dr Anatoliy Reutskiy Association of Family Doctors Kaliningrad, Russia Dr Carl Llor Spanish Society of Family Medicine Barcelona, Spain Dr Beatriz Gonzáles Lόpez-Valcárcel University of Las Palmas de Gran Canaria Las Palmas, Spain Dr Justo Jesús Artiles Sánchez Consejería de Sanidad del Gobierno de Canarias Las Palmas, Spain Dr Lidia Caballero Misiones Association of General Family Medicine and Health Team Posadas, Argentina Dr Marit Rønning World Health Organization, Collaborating Centre for Drug Statistics Methodology Oslo, Norway Dr Christos Lionis World Organisation of Family Doctors in Europe c/o University of Crete Heraklion, Crete IPSE | 71

Improving patient safety in Europe

http://ipse.univ-lyon1.fr

BACKGROUND AIMS Considerable efforts have been made to IPSE aimed to reduce significant dif- date to harmonise data on nosocomial ferences that persist in the risks as- infections (NI) and antibiotic resistance (AR) sociated with HAI and AR in the in Europe. As a result, large variability in healthcare of countries in Europe. preventive practices and outcomes across countries has become evident. Based on EXPECTED this experience, the IPSE project aimed AND OBTAINED RESULTS at resolving these persisting differences IPSE results include the following: through the following approaches: harmonisation and support for providing health services with timely professional profiles and training information, evidence-based guide- for infection control practitioners; lines and educational tools to manage European standards and indicators for effectively the risk of NI and AR; public health surveillance and guide- strengthening the status of profession- lines for the control of HAI and AMR; als involved in infection control activities; event warning and rapid ex- fostering the control of the emer- change on NI and AMR; gence and spread of multiple resist- sustaining and extending HELICS ant organisms in the intensive care NI surveillance in Europe; unit (ICU) through an integrated improving surveillance and control surveillance programme; of antibiotic resistance and hygi- monitoring the level of achievement of enic precautions in the ICU; the NI and AR control programmes. understanding the interaction of antibiotic consumption, infections Problem: and resistance patterns in the ICU; Considerable efforts have been made to date feasibility of surveillance of HAI in Euro- to harmonise data on healthcare-associated pean nursing homes and home care. infections (HAI) and antimicrobial resistance (AMR) in Europe. As a result, large vari- Project Coordinator ability in preventive practices and outcomes Prof. Jacques Fabry across countries has become evident. Université Claude Bernard Lyon1 Laboratoire d’épidémiologie et Santé publique 8, avenue Rockefeller 69373 Lyon, France Tel: +33/4-78.77.75.99 Fax: +33/4-78.00.93.86 E-mail: [email protected]

 Project number: 2004216  EC contribution: €1 006 916  Duration: 36 months  Type: Grant Agreement  Starting date: 1 January 2005 72 | IPSE

Partners Ms Ana Paula Coutinho WHO, Copenhagen, Denmark Dr. Hajo Grundmann National Institute for Public Health and the Environment Bilthoven, Netherlands Dr. Carl Suetens L’Institut scientifique de Santé publique Brussels, Belgium Dr. Hakan Hanberger Swedish Institute from Infectious Disease Control Solna, Sweden Prof. Uwe Frank Universitätsklinikum Freiburg Freiburg, Germany Dr. Maria Luisa Moro Regione Emilia-Romagna – Agenzia Sanitaria Regionale Bologna, Italy Dr. Andreas Voss European Society of Clinical Microbiology and Infectious Diseases Taufkirchen, Germany Prof. Barry Cookson Health Protection Agency London, England, UK LeishEpiNetSA | 73 Control strategies for visceral leishmaniasis (VL) and mucocutaneous leishmaniasis (MCL) in South America: applications of molecular epidemiology

BACKGROUND EXPECTED RESULTS The LeishEpiNetSA project involves A range of new epidemiological tools comparative investigations between will be produced. Distribution of drug- endemic areas for visceral leishmaniasis resistant genotypes will be mapped. A (VL) and mucocutaneous leishmania- wealth of data will be deposited in a new sis (MCL) in Paraguay, Peru, Brazil and database, linked to a European database. Venezuela, and will strengthen lo- An expanded South American repository cal capacities for research and Latin for Leishmania will be established and American-European collaborations. cooperation will be improved between South American researchers. A series of LeishEpiNetSA will develop a full range publications and reports will be written to of microsatellite markers and multi-locus disseminate findings from the project. sequencing typing (MLST) of housekeep- ing genes for the Leishmania brazilien- Potential applications: sis complex and for L. guyanensis. It Improved strategies for surveillance and will also establish in South America the control, with consequent benefits to public procedures for microsatellite and MLST health and the alleviation of poverty. analysis for L. infantum, which have been developed and proven as epidemiologi- Project Coordinator cal tools by a European network. Prof. Michael A. Miles London School of Hygiene and Tropical Medicine Department of Infectious and Tropical Diseases Problem: Keppel Street A full and detailed understanding of the London WC1E 7HT England, UK transmission cycles and molecular epide- Tel. +44 2079272340 miology of VL and MCL is necessary to E-mail: [email protected] develop disease control and surveillance. Partners AIMS Dr Gabriele Schoenian The overall aim is to apply molecular Charite Universitaetsmedizin Berlin Berlin, Germany methods to improve the understanding of the epidemiology of the subgenus Vian- Dr Carmen Canavate Instituto de Salud Carlos III nia and L. infantum in South America. Madrid, Spain Dr Jean-Claude Dujardin Prinz Leopold Instituut voor Tropische Geneeskunde Antwerp, Belgium

 Project number: 015407  EC contribution: €2 489 823  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2006 74 | LeishEpiNetSA

Dr Lenea Campino Universidade Nova de Lisboa/Instituto d e Higiene e Medicina Tropical Lisbon, Portugal Dr Semiramis do Monte Centro de Ciencias da Saude da Universidade Federal do Piaui Teresina, Piaui, Brazil Dr Rolando Oddone Universidad Nacional de Asunción Asunción, Paraguay Dr Jorge Arevalo Universidad Peruana Cayetano Heredia Lima, Peru Dr Maria Norma Melo Universidade Federal de Minas Gerais Belo Horizonte, Brazil Prof. Maria Dora Feliciangeli Universidad de Carabobo-Centro de Investigaciones Biomedicas Caracas, Venezuela Dr Elisa Cupolillo Sociedade de Promoção da Casa de Oswaldo Cruz Rio de Janeiro, Brazil Dr Joachim Clos Bernhard Nocht Institute for Tropical Medicine Hamburg, Germany MagRSA | 75 Fully automated and integrated microfluidic platform for real-time molecular diagnosis of methicillin- resistant Staphylococcus aureus http://www.MagRSA.org

BACKGROUND The diagnostic protocol relies on a new Methicillin-resistant Staphylococcus aureus and clinically validated procedure that (MRSA), a virulent organism resistant to consists of a direct one-step enrichment many drugs, is responsible for many nosoco- of S. aureus present in either nasal or mial and community-acquired infections. Ef- inguinal swabs, followed by DNA extrac- fective diagnostics is a strategic key element tion of immunocaptured bacteria and their in the campaign against the spread of MRSA, identification by multiplex sequence ampli- allowing better infection surveillance and fication using real-time quantitative PCR. control measures, as well as more efficient patient treatment and/or isolation options. Potential applications: MagRSA will develop a new diagnostics plat- MagRSA’s diagnostics platform will have form providing a fast, simple and accurate potential applications in molecular diag- identification of MRSA from clinical samples. nostics and be the most growing segment within the global in vitro diagnostics market. Problem: According to the World Health Organiza- Project Coordinator tion (WHO), resistance of Staphylococcus Prof. Jacques Schrenzel aureus to methicillin, its usual antibiotic, Geneva University Hospitals Division of Infectious Diseases - Genomic increased from 2% in 1975 up to 60% Research Lab today in some areas and no new antibiotic Rue Micheli-du-Crest 24 1211 Geneva, Switzerland is expected on the market for many years. Tel. +41 022 372 7301 Fax +41 022 372 7304 AIMS E-mail: [email protected] MagRSA seeks to develop a new diag- Partners nostics platform that will provide a fast, Dr Amar Rida simple, automated and accurate identifica- Spinomix SA Lausanne, Switzerland tion of MRSA from clinical samples. The simplicity of the proposed technology Dr Neven Zoric TATAA Biocenter AB concept — integrating cost-effective and Göteborg, Sweden widely available components — allows Dr Felix von Stetten for the provision of low cost systems, a Institute of Microsystem Technology (IMTEK) prerequisite condition for the large adop- at the University of Freiburg Freiburg, Germany tion of molecular tests by hospitals. Dr Manuel Gaboyard ADEMTECH SA EXPECTED RESULTS Pessac, France Procedure improvement: The steps Dr Mabel Perrin of the diagnostic protocol were sig- SCIPROM SàRL nificantly improved in terms of spe- St-Sulpice, Switzerland cificity, sensitivity and turn-around time (three hours instead of six hours) and relies on the following steps:

 Project number: LSHM-CT-2006-037957  EC contribution: €2 095 800  Duration: 36 Months  Type: Specific Targeted Research Project  Starting date: 1 October 2006 76 | MalariaPorin Validation of the plasmodium aquaglyceroporin as a drug target

http://ec.europa.eu/research/health/infectious-diseases/poverty-diseases/projects/99_en.htm

BACKGROUND that determine pore selectivity, identi- Malaria is one of the three major infectious fied therapeutically targetable aquaporin diseases. Although the disease is prevalent structures, and established solid and in the tropics and subtropics, it has caused usable assay systems for testing poten- a global emergency. Between 300 to 400 tial aquaporin blockers, among others. million cases with 1 million to 2 million deaths are recorded each year. A rapidly Potential applications: increasing resistance to antimalarial drugs PfAQP has the potential to be used as a calls for focused novel strategies to combat target for malaria treatment. It is further en- the disease. MalariaPorin is an interdisci- visioned that MalariaPorin may become the plinary project aimed at taking genomic starting point for a wider strategy to assess information forward to drug development. the role of aquaporins in pathogenic para- The Plasmodium falciparum genome sites, such as Toxoplasma gondii, Trypano- project aimed at the accelerated dis- soma brucei and Trypanosoma cruzi, covery of novel antimalarial drug tar- and their potential use as drug targets. gets. Using P. falciparum genome data, MalariaPorin identified a single water/ Project Coordinator glycerol channel (aquaglyceroporin of Prof. Dr Eric Beitz Plasmodium falciparum (PfAQP)) present University of Kiel at the parasite/host interface. It is the Pharmaceutical Institute Gutenbergstrasse 76 only member of the aquaporin family 24118 Kiel, Germany encoded in the P. falciparum genome. Tel. +49 431 880 1809 Fax +49 431 880 1352 AIMS E-mail: [email protected] The goals of MalarisPorin were to assess the suitability of PfAQP as an anti-malarial Partners drug target and generate the conditions Dr Jürgen Kun University of Tübingen for further development of such drugs. Tübingen, Germany OBTAINED RESULTS Prof. Stefan Hohmann University of Gothenburg Significant progress was made in various Gothenburg, Sweden areas related to the project, involving fields Prof. Sabine Flitsch as diverse as Plasmodium physiology, University of Manchester pharmaceutical chemistry and biophysics. Manchester, England, UK MalariaPorin provided first insights into os- Dr Bert de Groot and Dr Helmut Grubmüller motic protection systems of apicomplexan Max Planck Institute for Biophysical Chemistry intracellular parasites, obtained fundamen- Göttingen, Germany tal and novel data on glycerol metabolism Prof. Peter Agre and Prof. Nirbhay Kumar of P. falciparum, redefined known and Johns-Hopkins University School of Medicine specified new aquaporin protein structures Baltimore, Maryland, US

 Project number: LSHB-CT-2004-012189  EC contribution: €885 600  Duration: 27 months  Type: Specific Targeted Research Project  Starting date: 1 January 2005 MANASP | 77 Development of novel management strategies for invasive aspergillosis http://www.manasp.org

BACKGROUND Potential applications: The overall objective of the MANASP Incorporation of diagnostic tests will facili- project was to develop new treatment tate research trials of new antifungal agents strategies for Invasive Aspergillosis (IA) or other novel therapies, and wider applica- — the major infectious complication of tion of this technology will enable the treat- treating haematological malignancies with ment of other groups of patients (outside intensive chemotherapy or haematopoi- the Haematological Malignancy field). etic stem cell transplantation (HSCT). Project Coordinator AIMS Prof. Hermann Einsele The aims of MANASP included: University of Wuerzburg Medizinische Klinik II Klinikstrasse 6 – 8 development of immunothera- 97070 Wuerzburg, Germany peutic strategies for IA; Tel. +49 931 20170010 Fax +49 931 20136409 development of improved diagnostic E-mail: [email protected] tests for IA with commercial potential; validation of a dendritic cell (DC)-based Partners vaccine immunotherapy strategy in Dr Niklas Finnstrom animal models to generate protec- Sangtec Molecular Diagnostics tive immunity against Aspergillus; Bromma, Sweden use of genomic and proteomic Prof. Tom Rogers techniques to identify new As- Trinity College Dublin 8, Ireland pergillus targets that interact with the host’s immune system. Prof. Jean Paul Latgé Institute Pasteur Paris, France EXPECTED AND OBTAINED RESULTS Prof. Luigina Romani University of Perugia The results of the MANASP include: Perugia, Italy

Dr Jean Kadouche identification of different pattern recog- Monoclonal Antibody Therapeutics nition receptors in response to A. fumi- Evry, France gatus and their role in activating DCs; Prof. Axel Brakhage identification of PAMPs of A. fumigatus Leibniz Institute for Natural Product Research useful for immunotherapy strategies; and Infection Biology Jena, Germany characterisation of Aspergillus-specific T-cell response in healthy individuals; Dr Georg Rauser Miltenyi Biotec development of an assay to detect Bergisch Gladbach, Germany Aspergillus DNA with high specificity; Prof. Jean Marie François commercialisation of the assay into an Institut National des Sciences Appliquées affordable and rapid diagnostic test. Toulouse, France

 Project number: LSHM-CT-2006-037899  EC contribution: €2 914 800  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2007 78 | micro-MATRIX Workshop on strategies to address antimicrobial resistance through the exploitation of microbial genomics http://www.cnb.csic.es/~mvicente/full_book.pdf or http://www.cnb.csic.es/~mvicente/micro-MATRIX+cover.pdf BACKGROUND OBTAINED RESULTS Recent genomic technologies allow the The workshop conclusions were sum- study of global physiological processes in marised in a report (http://www.cnb.csic. microbes. Their application to the study of es/~mvicente/micro-MATRIX+cover.pdf) pathogens enables researchers to search submitted to the Commission. It provided a for new medicines to combat infection, roadmap to implement a research activity avoid the emergence of resistance against based on functional genomics to tackle the them, and help anticipate therapies for new problem of antibiotic resistance and discov- emerging diseases and devise treatments. ery. A summary of the report was presented Predictive microbiology may also be used at the PathoGenoMics ERA-NET Constitu- to anticipate the presence of unexpected ent Assembly in Berlin on 14 October 2004. potential pathogens. Both industrial and sustained public sector efforts are needed Potential applications: to fully develop the promising potential of Genomics can contribute to combating this research frontier of the microbial world. antibiotic resistance and comparative genomics yields information on the univer- Problem: sality of targets in important pathogens. The ability to effectively treat microbial Functional genomics helps us understand infections will reduce morbidity, and have how to avoid the path to resistance, a positive impact on health management and genomics research will contribute policies. The discovery of new antibacterial to increasing the amount of antibiotic agents against resistant micro-organisms is generated by the producer organisms. an urgent and vital need. The social costs incurred by the incidence of infectious Project Coordinator diseases in the population at large, and in Prof. Miguel Vicente Centro Nacional de Biotecnología CSIC particular the elderly and the productive age Darwin 3, Campus de Cantoblanco sectors, are enormous. Hospitalisation costs 28049 Madrid, Spain E-mail: [email protected] per patient run above about 500 € per day. Curbing the spread of resistant pathogens Partners will result in the attainment of high standards Prof. Eliora Ron in human health care, it will reduce social Tel-Aviv University Tel Aviv, Israel and public healthcare costs and will there- Dr. Cecília Arraiano fore have a beneficial impact on the citizens. ITQB Universidade Nova de Lisboa Lisbon, Portugal AIMS Dr. Garry Blakely The micro-MATRIX workshop aimed to University of Edinburgh discuss microbial functional genomics as Edinburgh, Scotland, UK a powerful and innovative tool; to discover Prof. Anthony Pugsley Institut Pasteur new cellular targets that would be used to Paris, France counteract bacterial resistance to anti- Dr. Antonio Martínez biotics; and to further avoid the genera- PROGENIKA Biopharma SA tion and spread of new resistances. Derio (Vizcaya), Spain

 Project number: LSSM-CT-2003-502801  EC contribution: €34 002  Duration: 9 months  Type: Specific Support Action  Starting date: 1st January 2004 MOSAR | 79 Mastering hospital antimicrobial resistance and its spread into the community http://www.mosar-sic.org

BACKGROUND spp. is desirable, the most appropri- Infections caused by antimicrobial-resistant ate strategies for control remain elusive. bacteria (AMRB) account for an increas- While interventions to reduce patient-to- ing proportion of healthcare-associated patient transmission are considered the infections in European hospitals, par- cornerstone of infection prevention, their ticularly in intensive care units (ICUs). feasibility and cost-effectiveness have not Increased prevalence of resistance to been determined rigorously. Evidence from antibiotics in major hospital pathogens prospective, multi-facility studies regarding is associated with adverse outcomes of the relative efficacy and cost-effectiveness patients affected, and includes delayed of different control strategies is lacking. appropriate therapy or even failure of The lack of strong scientific support to therapy, as well as increased mortality. recommendations for control of AMRB substantially weakens their impact and While the optimal strategies for control of contributes to the marked heterogeneity of AMRB remain debated, understanding the preventive practices across institutions. dynamics of resistance and the relative contribution of the most important determinants AIMS of dissemination of AMRB (cross-transmis- The overall objective of MOSAR is to pro- sion via contacts and antimicrobial selec- vide advanced knowledge in the dynamics tive pressure), is needed to better define of transmission of AMRB, and address these strategies. The integration in these the controversies surrounding control approaches of rapid molecular diagnostic measures by testing different strategies testing for AMRB carriage may improve the to combat the emergence and spread timeliness and efficacy of control measures. of antimicrobial resistance, focusing on endemic or emerging AMRB in hospitals, Problem: now spreading into the community. Data gathered within the European Antimicrobial Resistance Surveil- EXPECTED RESULTS lance System (EARSS project) show The results anticipated by the MOSAR that resistance rates for major noso- partners include the following: comial pathogens have increased to alarming levels in many countries. 1. development of standards for conventional methods for detection Although most authorities agree that control of AMRB in screening samples; of AMRB such as MRSA, vancomycin- 2. development and validation in the resistant enterococci VRE, extended- clinical setting of high-throughput spectrum beta-lactamase (ESBL) producing molecular-based methods for detection Enterobacteriaceae, and Acinetobacter of resistant bacteria in screening for

 Project number: LSHM-CT-2007-037941  EC contribution: €10 000 000  Duration: 60 months  Type: Integrated Project  Starting date: 1 February 2007 80 | micro-MATRIX

carriage of AMRB in clinical samples, Partners and assessment of their cost-utility; Dr Didier Guillemot and Dr Patrick Trieu-Cuot 3. assessment from prospective, Institut Pasteur Paris, France multi-centre studies in areas with high prevalence of antimicrobial Prof. Herman Goossens University of Antwerp resistance, of the relative efficacy Antwerp, Belgium and cost-effectiveness of different Prof. Waleria Hryniewicz control strategies including National Medicines Institute enhanced standard precautions; Warsaw, Poland 4. development of mathematical models Prof. Jordi Vila integrating the contribution of the Institut d’Investigacions Biomèdiques August Pi I Sunyer intrinsic epidemicity of MRSA, of Barcelona, Spain cross-transmission and of antibiotic Prof. Marc Bonten and Dr Robert Veen use in the dynamics of resistance, to be University Medical Center Utrecht translated into user-friendly interfaces Utrecht, Netherlands for use by infection control personnel. Dr Stephan Harbarth University of Geneva Hospitals Potential applications: Geneva, Switzerland Results from MOSAR will inform health- Dr Yehuda Carmeli Tel Aviv Sourasky Medical Center care workers and decision-makers on Tel Aviv, Israel strategies for forecasting and mastering Dr Ben Cooper antimicrobial resistance. The project’s Health Protection Agency results should increase awareness of no- London, England, UK socomial pathogens such as vancomycin- Prof. Isabelle Durand-Zaleski resistant enterococci (VRE) as an emerging Université Paris Val de Marne cause of hospital acquired infections. Créteil, France Prof. Eric Fleury Institut National de la Recherche MOSAR will contribute to develop- en Informatique et Automatique (INRIA) ing the next generation state-of-the-art Villeurbanne, France technologies of diagnostic tests. Exist- Dr Jérôme Weinbach and Dr Delphine Sondaz ing molecular tests and the newly de- Inserm Transfert veloped technologies will be adapted to Paris, France the different needs of the laboratories Dr Camille Cyncynatus and countries participating in MOSAR. AbAg SA Chilly-Mazarin, France

Knowledge gained through MOSAR Dr Gerd Heinz BAG GmbH will help format education and training Lich, Germany of healthcare personnel and beyond. Dr Paul Wallace British Biocell International Ltd (BBI) Project Coordinator Cardiff, England, UK Prof. Christian Brun-Buisson Dr Guido Krupp Institut National de la Santé et de la Recherche AmpTec GmbH Médicale (INSERM) Hamburg, Germany INSERM U657 & Université Paris Val de Marne (UVPM) Dr Dirk Fischer Hôpital Henri Mondor, Array-on GmbH Assistance Publique-Hopitaux de Paris Gatersleben, Germany 51, Ave Mal De Lattre de Tassigny Créteil, France Tel. +33 1 4981 2391 Fax +33 1 4207 9943 E-mail: [email protected] NewHiv Targets | 81

Identifying novel classes of HIV inhibitors

BACKGROUND EXPECTED The objective of the NewHiv Targets AND OBTAINED RESULTS project was to design novel screen- The NewHiv Targets partners designed ing assays allowing the identification one cell-based assay that did not require of novel classes of HIV inhibitors. the use of infectious virus, allowing for the screening of chemicals libraries. As Problem: proof of concept, they screened 2 000 Despite the success of highly active compounds, and were able to identify antiretrovirals to control HIV replication one interesting hit. In secondary analysis in infected patients, at least in countries with infectious HIV, this compound dis- that can afford these treatments, new played very little antiviral activity. drugs are still needed. Widely used drugs The next aim was to extend the screening to mainly target two viral enzymes: reverse a higher number of compounds (2 libraries transcriptase and protease. However, of 20 000 and 4 000 compounds. The part- about 20% of patients cannot tolerate ners sought to further document the activity antiviral cocktails in the short term, and of the first hit. More fundamentally, they are long-term treatments are often associ- studying the mechanisms of HIV-1 assembly ated with severe side effects. There and transfer through cell-to-cell contact. is also increasing concern about the spread of drug-resistant HIV variants. Potential applications: Identification of novel antiviral treatment. AIMS The project partners aimed to identify Project Coordinator lead compounds that could impact HIV Dr. Olivier Schwartz through new mechanisms. Academic Institut Pasteur 25-28 rue du Dr Roux experts in virology and cellular biology 75015 Paris, France joined forces with antiviral-research Tel. +33 145688353 E-mail: [email protected] specialists and pharmacologists to perform anti-HIV high-throughput screen- Partners ing (HTS) assays. The partners defined Dr. Kalle Saksela one unexploited viral target, for which University of Tampere there are no available inhibitors: the Tampere, Finland critical step of viral release from the cell. Dr. Barbara Mueller University Clinic of Heidelberg This novel target was chosen because Heidelberg, Germany important recent discoveries have shed Dr. Maurizio Federico new light into the molecular mechanisms Laboratory of Virology of virus budding, thereby rendering Istituto Superiore di Sanita Rome, Italy this critical step in the HIV lifecycle a Prof. Marcel Hibert feasible target for drug development. Université Louis Pasteur Strasbourg, France

 Project number: LSHP-CT-2004-012169  EC contribution: €550 000  Duration: 24 months  Type: Specific Targeted Research Project  Starting date: 1 January 2005 82 | NEWTBDRUGS New drugs for persistent tuberculosis: exploitation of 3D structure of novel targets, lead optimisation and functional in vivo evaluation

BACKGROUND synthetic chemistry and functional evalua- Tuberculosis (TB) is one of the most deadly tion of best hits in in vivo animal models. infectious diseases in the world. The high rates of patient non-compliance lead not EXPECTED only to more than 3 million deaths per year, AND OBTAINED RESULTS but also to the creation of chronic, infec- This study made a number of sci- tious, drug-resistant TB strains, against entific breakthroughs including: which almost all existing antibiotics are ineffective or prohibitively toxic. The out- solution of the 3D structure of come of the NEWTBDRUGS project would several persistence-related drug lead to new drugs that would shorten the targets of M. tuberculosis; duration of TB treatment, improve latent development of new assays for screening TB infection treatment and be effective drugs that kill persistent M. tuberculosis. against multidrug-resistant TB (MDR-TB). Potential applications: Problem: At least one of the leads identified The key problem in TB treatment is the and developed in this project will en- six- to eight-month-long treatment duration, ter clinical trials in humans for treat- which often leads to non-compliance. Pa- ing persistent TB, in cooperation with tients frequently get better quickly on an in- pharmaceutical companies active in tense course of antibiotic chemotherapy and manufacturing the existing TB drugs. therefore stop taking the drugs before the infection is eliminated. MDR-TB has become Project Coordinator a major health problem, not only in develop- Dr. Mahavir Singh LIONEX Diagnostics and Therapeutics GmbH ing countries but also in neighbouring coun- Inhoffenstrasse 7 tries of the European Community. In the face 38124 Braunschweig, Germany Tel. +49 5312601266 of the HIV/AIDS epidemic, new ‘sterilising’ Fax +49 5312601159 drugs with shorter regimens are needed that E-mail: [email protected] can significantly increase patient compli- Partners ance, substantially reduce the rate of emer- A.F.R.M. Coates gence of antibiotic resistance, materially St George’s Hospital Medical School decrease the costs of treatment and prevent London, England, UK progression from latent infection to active Prof. Gunter Schneider Karolinska Institutet disease. New strategies are urgently needed Stockholm, Sweden for combating the problems of TB treatment. Prof. Marcus Kalesse University of Hanover AIMS Hanover, Germany The NEWTBDRUGS consortium aimed Prof. Paul Driscoll to apply their integrated strategy of drug University College London London, England, UK development by structural analysis of Dr. Hans-Jürgen Hecht novel targets, virtual and real screening- GBF – German National Centre for Biotechnology based identification of leads, new organic Braunschweig, Germany

 Project number: LSHP-CT-2005-018729  EC contribution: €1 800 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 September 2005 NM4TB | 83

New medicines for tuberculosis

http://www.nm4tb.org

BACKGROUND partners will employ the most innova- New Medicines for Tuberculosis (NM4TB) tive approaches to identify and validate aims to successfully develop new drugs for targets for new drugs, and implement the the treatment of tuberculosis (TB) through screening and medicinal chemistry proc- an integrated approach implemented by esses required to identify lead compounds a team that combines some of Europe’s for the generation of candidate drugs. leading academic TB researchers with a major pharmaceutical company and AIMS three small to medium-sized enterprises NM4TB aims to successfully develop (SMEs), all with a strong commitment to new drugs for the treatment of TB with discovering new anti-infective agents. the following desired properties: NM4TB has a comprehensive portfolio of potential and validated targets, plus high potency to reduce treat- several novel, proprietary anti-TB agents ment duration; in its drug development pipeline. Among activity against persistent bacilli; the validated targets are several enzymes inhibition of new target classes; involved in highly druggable areas such as activity against multidrug resistant TB; cell wall biogenesis, nucleic acid synthesis specificity for Mycobac- and central metabolic pathways for which terium tuberculosis. assays amenable to high-throughput screening are available. Intensive efforts EXPECTED RESULTS will focus on rapidly emerging targets that The NM4TB consortium antici- impact upon two as yet untouched areas pates the following results: of the physiology of M. tuberculosis signal transduction pathways and persistence. development and implementation of novel enabling technologies Problem: required for drug development. TB is one of the oldest diseases known target validation in well-estab- to man and has infected one third of the lished, ‘druggable’ areas such as world’s population. As a result, someone the central metabolism, cell wall dies from the disease every 15 seconds and nucleic acid synthesis; and 30 million more people will lose their generation of the structural in- lives to TB in the next decade. Although formation for as many targets as directly observed short-course chemo- possible, acting iteratively in the therapy is available to treat the disease, drug development process. this treatment is old, slow and inefficient assay development and screening of by the current standards of the phar- deep chemical libraries encompass- maceutical industry. Here, the project ing ‘Active’ to ‘Hit’, ‘Hit’ to ‘Lead’

 Project number: LSHP-CT-2005-018923  EC contribution: €11 070 000 (original funding of €10 870 000, plus €200 000 from 2006 Targeted Top Up Call)  Duration: 60 months  Type: Integrated Project  Starting date: 1 January 2006 84 | NM4TB

progression; ‘lead’ optimisation activi- Dr Ida Rosenkrands ties that give rise to candidate drugs. Statens Seruminstitut, Department of Infectious Disease Immunology Copenhagen S, Denmark Potential applications: Dr Ute Möllmann The proposed research will result in: Hans-Knöll-Institut für Naturstoff-Forschung Jena, Germany the development of new technologies Prof. Andrew Munro and assays for TB drug development; University of Manchester Manchester, England, UK the discovery of new classes of lead compounds for fighting TB; Dr Katarina Mikusova Comenius University the lead optimisation and progres- Bratislava, Slovakia sion to candidate drug status. Prof. Michael Arand University of Zurich Project Coordinator Zurich, Switzerland Prof. Stewart T. Cole Prof. Kéri György Unité de Génétique Moléculaire Bactérienne Vichem Chemie Research Ltd Institut Pasteur Budapest, Hungary 25-28, rue du Docteur Roux 75724 Paris, France Dr Daniela Jabes Tel. +33 145688446 NeED Pharmaceuticals Fax +33 140613583 Cassina Rizzardi, Como, Italy E-mail: [email protected] Prof. Philip Butcher St. George’s Hospital Medical School Partners London, England, UK Prof. Alwyn T. Jones Dr Mamadou Daffé Uppsala University Institut de Pharmacologie Uppsala, Sweden et de Biologie Structurale Dr Tanjore Balganesh Toulouse, France AstraZeneca R & D Bangalore, India Prof. Tanya Parish Barts and the London Queen Mary’s School of Medicine and Dentistry London, England, UK Prof. Kai Johnsson Ecole Polytechnique Fédérale de Lausanne Lausanne, Switzerland Prof. Giovanna Riccardi Università degli studi di Pavia Pavia, Italy NPARI | 85 Tailoring of novel peptide coatings and therapeutics derived from a newly identified component of the human innate immunity against resistant infections http://npari.org/

BACKGROUND 5. Pharmacological and efficacy evaluation The apoE and apoB human proteins have of peptides in a range of models. recently been linked to the innate immune 6. Efficacy data for candidate coatings system. Peptide sequences derived from in dynamic biofilm models. these proteins have been shown to have varied anti-infective properties that can Potential applications: be modified by small changes to the core The exploitation of this new class of peptide sequence. Thus, the apoE and antimicrobial peptides offers the po- apoB peptides exhibit antibacterial, anti- tential to develop new therapeutics fungal and antiviral properties, and present against a range of the most resistant and an excellent opportunity to develop novel problematic organisms facing Euro- therapeutics and medical device coatings. pean infectious disease clinicians.

Problem: SME Participation Despite major advances made in the A vital component to the project is the development of numerous classes of participation of several small and medium- antimicrobial agents to treat serious sized enterprises (SMEs) who have exper- life threatening infections, microorgan- tise in the fields of drug development. This, isms are becoming increasingly resist- combined with the academic expertise ant to the agents developed by man. of the remaining partners, allowed for an experienced and focused consortium. AIMS The aims of the NPARI consortium were Project Coordinator to fully exploit the exciting properties of Dr Mike Birch this novel peptide class. Specifically, the F2G Ltd Po Box 1, Lankro Way, Eccles consortium aimed to target peptide se- Manchester, M30 OBH quences into two areas: coating agents for England, UK Tel. +44 161 785 1277 medical devices and therapeutics agents. Fax +44 161 785 1273 E-mail: [email protected] EXPECTED Partners AND OBTAINED RESULTS Dr Christophe d’Enfert and Dr Jean-Marc Ghigo 1. The design of a small peptide library Institut Pasteur tailored to the proposed exploitable Paris, France application of the project. Dr Chiara Bigogno 2. Determination of the activity NiKem Research s.r.l. spectrum of active peptides and Baranzate (Mi), Italy ranking of peptide variants. Prof. Niels Høiby University Hospital of Copenhagen 3. Optimisation and toxicity Copenhagen Ø, Denmark. profiling of active peptides. Dr Curtis Dobson 4. Efficacy profiles against a panel of Ai2 Ltd resistant organisms growing as biofilms. Manchester, England, UK

 Project number: LSHM-CT-2006-037692  EC contribution: €2 800 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 December 2006 86 | Phagevet-P

Veterinary phase therapies as alternatives to antibiotics in poultry production

http://www.ceb.uminho.pt/projectos/PhageVet-P/

BACKGROUND The first scientific objective is to es- Phages are very specific in killing a tablish that in live poultry, treatment limited range of bacterial strains, cf. with specific phages can reduce or antibiotics, and do not cause infec- eliminate the occurrence of the two tions of animals or plants. Studies have pathogens responsible for the major- shown phages to be effective in removing ity of human food-borne illness, namely contamination from poultry carcasses, Salmonella and Campylobacter spp. and in killing pathogens in the intestinal tract of live poultry and in eggs. The second major objective is to establish that this protection of the live The Phagevet-P project focused on trials birds from infection, provides poultry in live poultry to evaluate the importance of products for human consumption that safety and quality factors including phage have greatly reduced contamination choice and production, and modeling of levels with these two pathogens. the infection and curing process. Alterna- tive strategies were also considered for po- OBTAINED RESULTS tential constraints related to development of The lytic spectra of the phages were deter- phage-resistant strains of pathogens, mass mined on a group of more than 200 clinical application causing environmental con- and food isolates of different serotypes of cerns, and destruction of phages by stom- both pathogens. The genomes of some of ach acidity following oral administration. the Salmonella phages were examined and shown not to carry any Salmonella genes, Problem: indicating a very low likelihood of carriage Antibiotics are currently being phased out and potential transfer of pathogenic traits. of food animal production but alternative In vivo trials showed that the phages select- methods are needed to combat bacterial ed and characterised offer a good potential diseases in food animals, and to control to control Salmonella and Campylobacter transmission of pathogens responsible in vivo, but its efficacy is time dependent. for food-borne illnesses to humans. Potential applications: AIMS Reduction or elimination of the widespread Phagevet-P aimed to evaluate the potential use of antibiotics in poultry feed and use of phages as alternatives to antibiotics replacement by prophylactic application in poultry production and to characterise of phages in large-scale poultry rearing. the efficacy of phages from farm-to-fork.

 Project number: 2005-7224  EC contribution: €674 026  Duration: 36 months Type: Specific Targeted Research Project  Starting date: 1 May 2005 Phagevet-P | 87

Project Coordinator Dr Joana Azeredo Universidade do Minho Departamento de Engenharia Biológica Braga, Portugal E-mail: [email protected]

Partners Dr Evangelia Komitopoulou Leatherhead Food International Ltd Leatherhead Surrey, England, UK Dr Paul Gibbs Universidade Católica Portuguesa Porto, Portugal Dr Ben Gannon University of Bristol Langford Bristol, England, UK Dr Jaime Fabregas Universidad de Santiago de Compostela Santiago de Compostela, Spain Dr Victor N. Krylov State Institute for Genetics and Selection of Industrial Microorganisms Moscow, Russia 88 | PNEUMOPEP New methods of treatment of antibiotic-resistant pneumococcal disease

http://www.pneumopep.com

BACKGROUND Problem: The advances of the PNEUMOPEP S. pneumoniae imposes a huge disease project were new targets, identification of burden on humans: it is the number one completely new lead compounds, a new cause of pneumonia and it is the second approach to adjunctive therapy and a new most common cause of meningitis. method of delivery of the compounds. AIMS Streptococcus pneumoniae (S. pneumo- PNEUMOPEP aimed to identify small niae) imposes a huge disease burden on molecules and peptides that inhibit the humans. There is a pandemic of multi- activity of pneumolysin on pneumococ- drug resistant pneumococci and treat- cal surface proteins, in vitro and in vivo. ment is compromised. Even if antibiotics kill the bacterium, they can fail to prevent OBTAINED RESULTS death from neurological damage after The consortium obtained lead compounds meningitis, due to the acute toxaemia. for development of pneumococcal drugs.

The first event in toxaemia is the release Potential applications: of pro-inflammatory or toxic penumo- The results of the project would coccal products, probably exacerbated contribute to the treatment of by antibiotics. The pneumococcal toxin pneumococcal diseases. pneumolysin fulfils both definitions: it is directly toxic to mammalian cells Project Coordinator and it stimulates the release of inflam- Prof. Peter Andrew University of Leicester matory mediators from host cells. Department of Infection, Immunity and Inflammation Maurice Shock Building For this reason and because the toxin is University Road essential for the survival of the bacterium Leicester, LE1 9HN, England, UK Tel. +44 1162522941 in vivo, pneumolysin was a target for this Fax +44 1162525030 project. A second target was the cell sur- E-mail: [email protected] face proteinases involved in adhesion and invasion, which are important virulence Partners factors for the pneumococcus. These Dr Marco Oggioni Università di Siena proteins represented new targets and Siena, Italy their validation as targets was completed. Prof. Gio Teti University of Messina The new treatment will be based on Messina, Italy binding peptides isolated from a se- Dr Inder Gill Archimedes Development Ltd ries of large phage display libraries Nottingham, England, UK or based on small molecules identi- Dr Thierry Jarosz fied by high throughput screening. Cegedim Strategic Data Boulogne-Billancourt, France

 Project number: LSHM-CT-2005-512099  EC contribution: €1 500 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 June 2005 PREVIS | 89 Pneumococcal resistance epidemicity and virulence – an international study

http://www.previs.net

BACKGROUND effective antibiotic therapy. For decades, PREVIS provided an integrated platform to penicillin has been the drug of choice for study important and unexplored aspects treating pneumococcal infections, but of pneumococcal disease/pathogenesis, increasing levels of penicillin resistance, epidemiology/transmission and molecular up to 50% in some areas, has resulted mechanisms for resistance develop- in the use of alternative antibiotics ment.and even if the program now has come to an end the network will continue Properties affecting virulence of the organ- to study invasive disease potential in a ism, such as adherence, invasion and collected study from all the countries transmission of the bacteria, and human as well as pneumococcal meningitis in host factors have to be investigated and Europe. Hence the project has created correlated to the development of resist- novel interactions and collaborations ance and to the acquisition of resistance that will continue even after the funding markers. Also, antibiotic consumption has ceased from the EU commission may be an important factor affecting transmission and selection for resistance Problem: determinants. A better knowledge of Streptococcus pneumoniae remains molecular mechanisms involved in resist- among the most important causes of ance and of host-pathogen interactions life-threatening community-acquired dis- affecting pneumococcal infections would eases such as pneumonia, septicemia and lead to improved intervention, prevention meningitis, particularly in high risk groups and treatment strategies of these com- such as young children, HIV+ individuals mon community acquired infections. and the aged. The annual global mortality rate is over one million. Streptococcus AIMS pneumoniae is also the major cause of The objectives were to examine: upper respiratory tract infections (URTI) such as otitis media, and URTIs are one survival and growth in the antibiotic rich of the most common reasons for visits to milieu making it essential that bacteria doctor´s offices and for antibiotic prescrip- acquire genetic traits of resistance; tions. As many as 60% of healthy children successful drug-resistant strains to attending day-care centers have been compete with other members of the found to be colonized with pneumococci in species for colonisation, geographic the nasopharynx, which therefore appear spread and disease in the human host. to be a main reservoir for this pathogen. Drug resistant clones (DRPn) emerging from this major ecological reservoir are widely spread in Europe, threatening

 Project number: LSHM-CT-2003-503413  EC contribution: €3 000 000  Duration: 42 months  Type: Specific Targeted Research Project  Starting date: 1 January 2004 90 | PREVIS

OBTAINED RESULTS Prof. Regine Hakenbeck Results of PREVIS include: University of Kaiserslautern Kaiserslautern, Germany Prof. Hans Wolf-Watz non-typeable pneumococci (NTPn) Innate Pharmaceuticals have diverse genetic backgrounds; Umeå, Sweden a novel bacterial factor — pilus — is Dr Thorolfur Gudnason important for colonisation, virulence and National Vaccination Program - the inflammatory response in mice; Directorate of Health Reykjavik, Iceland TLR(toll-like receptor)9 deficient macrophages are defective in pneu- Prof. Jonas Almeida Instituto de Biologia Experimental e Tecnológica mococcal phagocytosis and killing. Lisbon, Portugal Dr Pavla Urbaskova Project Coordinator National Institute Public Health Prof. Birgitta Henriques Normark Prague, Czech Republic Swedish Institute for Infectious Disease Control 171 82 Solna, Sweden Tel. +46 84572300 Fax +46 8302566 E-mail: [email protected] Partners Dr. Katarzyna GrabowskaSwedish Institute for Infectious Disease Control Solna, Sweden Prof. Hermínia de Lencastre Instituto de Tecnologia Química e Biológica (ITQB) Oeiras, Portugal Prof. Brian Spratt Imperial College London, England, UK Prof. Karl G. Kristinsson and Prof. Ingileif Jonsdottir Landspitali University Hospital Reykjavik, Iceland Dr José Melo Cristino Instituto de Medicina Molecular Lisbon, Portugal Prof. Staffan Normark Karolinska Institutet Stockholm, Sweden READ-UP | 91

Redox antimalarial drug discovery

http://www.ird.fr/read-up/spip.php?rubrique3

BACKGROUND and in vivo studies led to the identification of Malaria remains one of the most devastating one hit. Based on the excellent in vitro and diseases of the developing world, causing in vivo results already obtained, READ-UP more than 1 million deaths and 300 million will develop new structural analogues using to 500 million clinical cases each year. Al- the same innovative approach. The in vitro though four Plasmodium species infect hu- and in vivo results obtained will be further mans (P. falciparum (P. f.), P. vivax, P. ovale improved by the application of optimisation and P. malariae), most deaths are caused techniques, through the ‘Drug Discovery’ by the severe complications of P. f. malaria. process that the READ-UP partners will Malaria-related morbidity and mortality are implement. Moreover, the READ-UP in- increasing mainly as a consequence of drug novative strategy should allow designing resistance as observed with the two most chemically stable compounds, which may widely used antimalarial drugs: chloroquine have a longer duration of action in vivo. and sulfadoxine-pyrimethamine. To combat malaria, new drugs are urgently needed. Potential applications: Application of READ-UP scientific break- The READ-UP project targeted the throughs into approved new medicines. identification of a new drug candidate for malaria. Starting from one series with Project Coordinator antimalarial activity, the project would Dr. Serge Petit realise hit-to-lead optimisation through Idéalp’ Pharma/IDEALP Bât. CEI – 66 molecular modelling, testing of new Bd Niels Bohr - BP 2132 chemical entities in vitro and in vivo and 69603 Villeurbanne, France Tel. +33 437488800 pharmacological, pharmacokinetics, Fax +33 478935653 toxicological and mechanisms studies. Partners Prof. Françoise Nepveu AIMS Université Paul Sabatier (UPS) Following the drug discovery proc- Toulouse, France ess until the pilot-scale production, the Prof. Paolo Arese objective was to propose one antima- Università di Torino Turin, Italy larial drug candidate with two back- ups for further pre-clinical studies. Dr. Livia Vivas London University London, England, UK EXPECTED Dr. Leonardo Basco AND OBTAINED RESULTS Organisation de Coordination pour la lutte contre An initial series of new stable compounds les Endémies en Afrique Centrale (OCEAC) Yaoundé, Cameroon was developed. In a first synthetic series, Dr. Laurence Touchard-Nicod several compounds presented anti-plas- ACIES modial properties and preliminary in vitro Lyon, France

 Project number: LSHP-CT-2005-018602  EC contribution: €2 000 000  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 December 2005 92 | REBAVAC Novel opportunities to develop vaccines to control antibiotic resistant bacteria: from the trials back to the laboratory

http://www.altaweb.eu/rebavac

BACKGROUND providers, industry representatives and pub- Antibiotic resistant bacteria are rapidly lic health experts to discuss critical issues. spreading worldwide, making it increasingly difficult to treat infections in large communi- EXPECTED ties as well as creating a major public health AND OBTAINED RESULTS problem. Vaccination is proposed as one of The workshop provided European research- the best tools to stop the spread and devel- ers with the newest trends and direc- opment of antimicrobial resistant micro-or- tions of research in the area of vaccines ganisms. However, the analysis of the effects to antibiotic-resistant bacteria. It was a of using conjugated vaccines against Strep- good occasion to envisage the exploita- tococcus pneumonia, Haemophilus influen- tion of new vaccination strategies. zae b and Neisseria meningitidis has shown some paradoxes and some interesting The outcomes of the workshop are expected aspects that led to a re-thinking of how im- to compel the European research and indus- munity to polysaccharide is elicited following try to move towards more efficient/efficacious vaccination and how memory is acquired. vaccines and vaccination strategies, and to find novel immunisation ways to optimise The workshop proposed by REBAVAC the use and formulation of currently avail- — involving some of the most important able vaccines to fight antibiotic resistance. experts in vaccination, immunology and bacterial resistance — represented a very Potential applications: important opportunity in Europe to discuss The impact of the scientific workshop the implication of the results of ongoing re- and of the correlated activities planned by search on the use and development of vac- REBAVAC is expected to be very strong cines to fight antibiotic resistant bacteria. in the field of developing new strategies against antibacterial resistant infections. Problem: Staphylococci and vancomycin-resistant The involvement of the European industry and Enterococci are causing nosocomial research groups in the vaccine field should infections, while other pathogens like fuel the design of novel vaccination strategies, pneumococcus, effectively treated in leading to improved control of infectious dis- the past with penicillin, are now resist- eases and stronger well-being for everyone. ant to a broad spectrum of antibiotics. Project Coordinator AIMS Dr Aldo Tagliabue The overall aim of REBAVAC was to CEO ALTA Srl Via Fiorentina 149 organise a European workshop in which 53100 Siena, Italy worldwide leading experts in vaccine re- Tel. +39 057750518 Fax +39 0577593815 search and immunology met with healthcare E-mail: [email protected]

 Project number: LSHM-CT-2006-037163  EC contribution: €121 200  Duration: 12 months  Type: Specific Support Action  Starting date: 1 September 2006 REPLACE | 93 Plants and their extracts and other natural alternatives to antimicrobials in feeds http://www.replace-eu.com

BACKGROUND animal products reaching the consumer, The EU banned growth-promoting including those from organic farming. antibiotics in 2006, and livestock producers need alternative ways of obtaining AIMS similar production benefits to maintain The overall aim is to derive safe alterna- profitability and competitiveness against tives to antimicrobials, based on plant overseas producers. Improving the health extracts and other natural materials. and safety of animal products reaching the consumer, including those resulting EXPECTED RESULTS from organic farming, is also important. The expected outcome will be a catalogue of plant extracts that can be used REPLACE is examining plants, plant as potential replacements for antibiotics extracts and other natural materials as in the animal feed industry. The major safe alternatives to feed antimicrobials. deliverables are to find natural materials The project will link fragmented research that suppress E. coli, Salmonella and C. carried out with different animal species perfringens infections, suppress parasites across Europe and provide a platform and their egg production in ruminants. for the rational production of a new generation of natural feed additives. Potential applications: The generated knowledge will allow Problem: the project results to achieve market The main fear was that antibiotic re- penetration for the new or modified sistance would arise from the use of products, and provide safe alterna- antibiotics in animals, and in turn possibly tives to former feed additives. transmit this resistance to human pathogens. Anthelmintics are also becoming Project Coordinator increasingly problematic in preventing Prof. R. John Wallace parasitic infections, and safe alternatives Rowett Research Institute Gut Health Division are needed. Aquaculture is a growing Aberdeen, AB21 9SB, Scotland, UK sector within the EU and antimicrobials Telephone: +44 (0)1224 716656 email: [email protected] are common in combating the problems Or [email protected] associated with intensification. Finding a growth promoter of natural origin will have benefits for environmental safety and awareness as well as the meet- ing the demand for a healthier food chain. Ways must also be found to improve the healthiness and safety of

 Project number: FOOD-CT-2004-5064877  EC contribution: €2 922 713  Duration: 60 months  Type: Specific Targeted Research Project  Starting date: 1 March 2004 94 | REPLACE

Partners Prof. Klaus Becker University of Hohenheim Stuttgart, Germany Dr Secundino Lopez Universidad de Leon Leon, Spain Prof. Ian Givens University of Reading Reading, England, UK Dr Frank Jackson Moredun Research Institute Edinburgh, Scotland, UK Dr Bent Borg Jensen Aarhus University Tjele, Denmark Dr Alojz Bomba Pavol Jozef Šafárik University in Košice Košice, Slovakia Dr Magne Kaldhusdal National Veterinary Institute Oslo, Norway Prof. Andrzej Rutkowski August Cieszowski Agricultural University Poznan, Poland Dr Richard Murphy Alltech Ireland Ltd Dunboyne, Co. Meath, Ireland Dr Marco Frehner DSM Crina Gland, Switzerland SAFEWASTES | 95 Evaluating physiological and environmental consequences of using organic wastes after technological processing in diets for livestock and humans http://www.safewastes.info

BACKGROUND production by composting. SAFEWASTES The SAFEWASTES project targeted improved cooperation between industry the development of innovative bio- and academia, generating new employ- technology for processing and purify- ment in biotechnological processing. ing organic materials from the food and plant-based extracts industries. Project Coordinator Prof. Dr Chlodwig Franz University of Veterinary Medicine Problem: Institute for Applied Botany and Pharmacognosy The industrial processing of fruits and veg- Veterinärplatz 1 1210 Vienna, Austria etables as well as the extraction of herbs Tel. + 43 (1) 25077 - 3100 produces millions of tonnes of organic Fax + 43 (1) 25077 - 3190 waste, by-products and residues each E-mail: [email protected] year. These waste materials are costly and Partners contribute to environmental problems. Prof. Dr. Rudolf Bauer Karl-Franzens-Universität Graz Graz, Austria AIMS Dr Age Jongbloed SAFEWASTES aimed to find innovative Wageningen University and Research Centre ways for generating novel, high added val- Lelystad, Netherlands ue products, and to demonstrate that there Prof. Dr Reinhold Carle University of Hohenheim is potential in recycling their organic by- Stuttgart, Germany products for the purpose of producing new Prof. Spyridon Kyriakis products acceptable to all stakeholders. University of Thessaloniki Thessalonica, Greece OBTAINED RESULTS Prof. Bruno Stefanon University of Udine By-products of the plant processing industry Udine, Italy were (re-)extracted before and after enzy- Prof. Doriana Tedesco matic fermentation and investigated phy- Università degli Studi di Milano Milan, Italy tochemically, in vitro and partly also in vivo in farm animals. A remarkable antioxidant, Dr Joachim Erler Bionorica AG anti-inflammatory and anti-adhesive (antimi- Neumarkt, Germany crobial) activity was found in vitro and in vivo. Dr Geert Bruggeman Nutrition Science NV Drongen, Belgium Potential applications: Dr Gerd Schatzmayr The results of SAFEWASTES will help food Biomin GmbH manufacturers use scientific approaches Herzogenburg, Austria to meet consumer demands for safer, Prof. Wieslaw Oleszek higher-quality food. The project will also Institute of Soil Science and Plant Cultivation Puławy, Poland boost European competitiveness. Improved Dr. Andreas Moser recycling of organic wastes should reduce RTD Services the load on landfills and cut methane Vienna, Austria

 Project number: 513949  EC contribution: €2 200 000  Duration: 39 months  Type: Specific Targeted Research Project  Starting date: 1 April 2005 96 | SavinMucoPath Novel therapeutic and prophylactic strategies to control mucosal infections by South American bacterial strains http://www.lille.inserm.fr/site/avenir_sirard/page.asp?page=557

BACKGROUND and the development of novel thera- Enteric and respiratory diseases remain a peutic and prophylactic interventions. major cause of mortality during neonate life and childhood within developing countries. AIMS The SavinMucoPath project is focusing The main objectives are to fuel understand- on bacteria that enter through or colo- ing of the host-pathogen interaction and to nise enteric and respiratory mucosa, i.e. develop novel mucosa-specific thera- Streptococcus pneumoniae, Salmonella peutics and vaccines to control bacterial enterica serovar Enteritidis, and Bordetella infections. Our strategies are based on pertussis. The selected bacterial pathogens the exploitation of innate defence mecha- are associated with important rates of nisms triggered by pathogen conserved morbidity and mortality in South America, molecules and pathogen-specific factors. especially in young children and those in the low socioeconomic bracket. Moreover, EXPECTED RESULTS the strains and serotypes that cause infec- The consortium expects to identify tions are unique to the developing coun- molecules from the selected bacteria tries in this area and consequently, basic that activate specifically protective research and development of therapies mucosal innate immunity so as to block and vaccines tailored to these local strains infections at the port of entry of bac- have been deserted by the European and teria and stimulate antigen-specific North American scientific communities. responses through mucosal cells.

Problem: We will develop cell and rodent models for Mucosal tissues represent the major high throughput screening of pathogen sites of infection by pathogenic microbes components to ultimately bring candi- and the study of mucosal pathogens is date experimental immuno-interventions therefore relevant for combating infection against enteric and respiratory infec- and reinforcing immunity. Thus, enteric tions to clinical trials within the next FP and respiratory diseases remain a leading cause of mortality worldwide. This proposal Potential applications: focus on mucosal bacterial pathogens that SavinMucoPath should contribute to the are of main importance for public health development of appropriate treatment of in Latin America. The strategic objective the corresponding diseases, especially is to confront the emergency caused by during childhood. The project will have a specific strains of Streptococcus pneu- major impact in the field of development of moniae, Salmonella spp, and Bordetella mucosal immuno-stimulators – adjuvants pertussis – through the improvement of that specifically control mucosal infections. knowledge on molecular pathogenesis

 Project number: INCO-CT-2006-032266  EC contribution: €1 699 908  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 October 2006 SavinMucoPath | 97

This effort may have a “transdisease” impact on anti-microbial treatments and vaccine strategies for different infectious diseases. If successful, the screened molecules may have an impact on the overall existing vaccines and antibiotherapy. A successful outcome of SavinMucoPath will substantially contribute to the further development of innovative and effective projects against any neglected mucosal infections

Project Coordinator Dr Jean Claude Sirard INSERM, U801 Institut Pasteur de Lille Team of antimicrobial mucosal immunity 1 rue du Pr. Calmette 59021 Lille, France Tel. +33 320871076 E-mail: [email protected]

Partners Dr Martin Rumbo and Dr Daniela Hozbor Universidad Nacional de La Plata La Plata, Argentina Prof. Tracy Hussell Imperial College London, England, UK Prof. Wolf-Dietrich Hardt Eidgenossische Technische Hochschule Zurich Zurich, Switzerland Prof. José Alejandro Chabalgoity Universidad de la Republica Oriental del Uruguay Montevideo, Uruguay Dr Alexis Kalergis Pontificia Universidad Catolica de Chile Santiago, Chile Dr Augusto Pich Otero Instituto Biológico Argentino (BIOL) Buenos Aires, Argentina 98 | SIGMAL Targeting malaria transmission through interference with signalling in Plasmodium falciparum gametocytogenesis http://ec.europa.eu/research/health/poverty-diseases/projects/101_en.htm

BACKGROUND gametocytes, while in the bloodstream of Inhibiting the transmission of the ma- the human host. Although proteins that laria parasite from infected humans to the are specifically expressed at the onset of mosquito vector would be of considerable gametocyte formation have been char- interest in the context of malaria control, acterised, the molecular mechanisms especially for preventing the dissemina- controlling this phenomenon remain to tion of drug-resistant genotypes. Since be elucidated. It is likely that intracellular only sexual forms of the parasite (the signalling, and particularly the phosphoryla- gametocytes) are infective to the mosquito, tion of proteins, is involved in gametocyte blocking gametocytogenesis would prevent differentiation and further stages of the transmission. But the molecular control of sexual cycle. Indeed, reverse genetics data gametocytogenesis is not understood. Our generated within the SIGMAL consortium laboratories have independently brought have already identified protein kinases (the significant contributions to the charac- enzymes responsible for protein phospho- terisation of (i) components of signalling rylation) and other signalling molecules as pathways, some of which are likely to be in- essential for Plasmodium sexual develop- volved in parasite sexual differentiation, and ment. Interference with these enzymes may (ii) proteins expressed at the onset of game- provide lead compounds for the develop- tocytogenesis, such as Pfg27 and Pfs16. ment of transmission-blocking drugs. The SIGMAL project aimed to generate an integrated picture of the early events of AIMS sexual development at the molecular level. SIGMAL aimed to raise understanding of gametocyte formation, in particular Problem: by characterising the signalling path- Malaria is a major public health problem ways involved, and to identify inhibitors in most of the developing world, and the of protein kinases that may inhibit sexual morbidity and mortality burden inflicted by development of the parasite, and thus this disease on many developing countries interfere with malaria transmission. hinders socioeconomic development. The emergence and spread of malaria parasites OBTAINED RESULTS that are resistant to existing anti-malarials The SIGMAL partners obtained: also exacerbates this problem. A way to control the spread of drug-resistant improved knowledge of the basic biol- parasites would be to prevent transmission ogy of malaria parasites, particularly of the parasite from infected humans to the with respect to cell differentiation; mosquito vector. To infect a mosquito, the validation by reverse genetics of parasite must first develop into special- novel molecular targets for trans- ised sexual forms, the male and female mission-blocking intervention;

 Project number: LSHP- CT-2004 -012174  EC contribution: €969 000  Duration: 27 months  Type: Specific Targeted Research Project  Starting date: 1 March 2005 SIGMAL | 99

identification of protein kinase in

Potential applications: SIGMAL will provide a list of validated targets for transmission-blocking drugs in the context of anti-malarial chemotherapy.

Project Coordinator Prof. Christian Doerig INSERM U609 Wellcome Centre for Molecular Parasitology University of Glasgow Biomedical Research Centre 120 University Place Glasgow, G12 8TA, Scotland, UK Tel. +44 1413306201 Fax +44 1413305422 E-mail: [email protected] Partners Dr Pietro Alano Istituto Superiore di Sanita Rome, Italy Dr David Baker London School of Hygiene and Tropical Medicine London, England, UK Dr Laurent Meijer Station Biologique Roscoff, France Dr Amit Sharma International Centre for Genetic Engineering and Biotechnology New Delhi, India Dr Francis Mulaa University of Nairobi Nairobi, Kenya 100 | SLIC Biosensors in molecular diagnostics nanotechnology for the analysis of species-specific microbial transcripts

BACKGROUND EXPECTED Molecular diagnostics of microbial AND OBTAINED RESULTS pathogens is an integral part of modern The identification of the different bacterial medicine. The growing need for direct tmRNA transcripts would be achieved by genotyping and/or the screening of the displaying a library of nucleic acid cap- transcriptome calls for the development of ture probes on the SLIC. This will enable alternative technologies. The SLIC consor- species identification and discrimination tium planned to develop a cost-effective between one or more species present in the platform for the identification bacterial spe- sample if mixed species infection is present. cies based on the SLIC-Nanobiosystem. Since the detection equipment will be Using tmRNA transcripts of the bacterial based on electronics, the realisation ssrA gene, the project partners were able of miniaturised/compact and cost- to detect, quantify and identify bacterial effective instruments will be possible. species in a single homogenous assay format. The SLIC-Nanobiosystem Potential applications: consists of a self-assembled lipid bilayer The consortium’s approach will lay membrane that integrates a synthetic the foundation for a new generation of ligand-gated ion channel (SLIC). The multiparametric molecular testing sys- SLIC comprises a capture molecule that tems that will open novel opportunities can specifically bind a given analyte, a within the area of point-of-care applica- process that is monitored via electri- tions in the clinical diagnostics market. cal impedance spectroscopy. With this system, the effect from even a few Project Coordinator channels can be resolved, thus pro- Dr Solomzi Makohliso viding an ultra-sensitive, highly stable Ayanda Biosystems PSE Parc Scientifique EPFL and versatile biosensor platform. 1015 Lausanne, Switzerland Tel. +41 216938631 Fax +41 216938631 The consortium planned to employ tran- E-mail: [email protected] scripts (tmRNA) of the ssrA gene to identify bacterial species present in clinical sam- Partners ples. These transcripts occur in high abun- Dr Ants Kurg Estonian Biocentre dance and contain a core sequence that is Tartu, Estonia species specific, a feature that was used Prof. Horst Vogel to identify infectious disease pathogens. Ecole Polytechnique Fédérale de Lausanne Lausanne, Switzerland AIMS Majella Maher National University of Ireland, Galway SLIC targeted the development of a Galway, Ireland cost-effective platform for the iden- Prof. Gerald A. Urban tification of bacterial species based Albert Ludwigs Unversität Freiburg on the SLIC-Nanobiosystem. Freiburg, Germany

 Project number: 513771  EC contribution: €1 999 980  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 January 2005 StaphDynamics | 101 Functional genomic characterisation of molecular determinants for staphylococcal fitness, virulence and drug resistance http://www.staphdynamics.net

BACKGROUND EXPECTED RESULTS The spread, survival and prevalence of The StaphDynamics results include: antibiotic resistant clones of Staphylo- coccus aureus represent an important 1. identification of novel molecular problem for human health. It is crucial to signatures of resistant clones; determine the key parameters required for 2. identification and validation virulence, nasal colonisation and survival of novel targets for drug and in the environment in order to elucidate vaccine development;. how these combine to produce epidemic 3. development of informed strains. This requires a detailed knowledge strategies for combating resistant of the bacterial components necessary for clones at the European level. the above processes. The StaphDynamics project aims to define these bacterial com- Potential applications: ponents, which in themselves may form StaphDynamics will create an im- novel targets for prevention and control. portant knowledge base needed to foster European competitiveness in Problem: the area of antibiotics research. Infections with antibiotic resistant microorganisms dramatically decreases Project Coordinator the quality of life of patients and leads Prof. Jan Maarten van Dijl to a higher morbidity in specific risk University Medical Center Groningen (UMCG) Department of Medical Microbiology groups, such as the elderly, immune- Hanzeplein 1 suppressed patients and children. P.O. Box 30 001 9700 RB Groningen, Netherlands Tel. +31 503 633 079 AIMS Fax +31 503 633 528 The primary aim of StaphDynamics is to E-mail: [email protected] identify important molecular determinants for fitness, virulence and drug resistance of S. aureus that may serve as future targets for drug and vaccine development, and to fight staphylococcal infections.

 Project number: LSHM-CT-2006-019064  EC contribution: €2 375 000  Duration: 48 months  Type: Specific Targeted Research Project  Starting date: 1 April 2006 102 | StaphDynamics

Partners Prof. Dr Friedrich Götz University Tübingen Tübingen, Germany Prof. Jiri Doskar Department of Genetics and Molecular Biology Brno, Czech Republic Prof. Simon J. Foster University of Sheffield Sheffield, England, UK Prof. Dr Jörg Hacker and Dr Knut Ohlsen Institut für Molekulare Infektionsbiologie Würzburg, Germany Prof. Dr Michael Hecker and Dr Susanne Engelmann Ernst-Moritz-Arndt Universität Greifswald, Germany Dr Iñigo Lasa Universidad Publica de Navarra / Consejo Superior de Investigaciones Científicas Pamplona, Spain Prof. Tarek Msadek Institut Pasteur Paris, France Prof. Hajo Grundmann European Antimicrobial Resistance Surveillance System Bilthoven, Netherlands Dr Karl-Heinz Wiesmüller and Dr Renate Spohn EMC microcollections GmbH Tübingen, Germany Dr Tjibbe Bosma Biomade Technology Groningen, Netherlands Dr Carolin Petry Genmedics GmbH Tübingen, Germany Tat machine | 103

Functional genomic characterisation of the bacterial Tat complex http://www.tatmachine.net

BACKGROUND EXPECTED The bacterial protein secretion process AND OBTAINED RESULTS can benefit human health through the The deliverables of Tat machine include: biotechnological production of biopharmaceuticals, but secreted bacterial toxins development of super-secreting strains and virulence factors represent a major of B. subtilis and Streptomyces coe- threat as well. The Twin-arginine trans- licolor, capable of exporting heterolo- location (Tat) machinery represents a gous proteins with high efficiency; recently discovered yet widely conserved understanding of the overall role of Tat in system for bacterial protein secretion. a limited series of pathogenic bacteria; in-depth understanding of the Tat trans- The Tat machine project sought to eliminate location mechanism was achieved by a existing bottlenecks in the Tat nanomachine combined biochemical/genetic analysis that limit biopharmaceutical production in of the Tat translocation process. Bacillus, E. coli and Streptomyces, as well as to characterise the structure and func- Potential applications: tion of Tat nanomachines from selected Tat machine will provide solutions to Gram-positive and Gram-negative bacteria. the industry and create a knowledge base that will foster European com- Problem: petitiveness in the area of antibiot- The Tat protein transporter system dif- ics and biotechnology research. fers from all other known protein trans- locases. The system has significant Project Coordinator potential for biomedical and biotech- Prof. Jan Maarten van Dijl nological research and exploitation. University Medical Center Groningen (UMCG) Department of Medical Microbiology Hanzeplein 1 AIMS P.O. Box 30 001 9700 RB Groningen, Netherlands The aims of Tat machine included: Tel. +31 503633079 Fax +31 503633528 exploiting the unique abilities of the E-mail: [email protected] system for the production of biomedi- Management Assistant cally important, heterologous proteins; Dr S. Bron University of Groningen Haren, Netherlands solving the three-dimensional (3D) structure of representa- tive Tat machines.

 Project number: LSHG-CT-2004-005257  EC contribution: €2 000 000  Duration: 48 months  Type: Specific Targeted Research Project  Starting date: 1 November 2004 104 | Tat machine

Partners Prof. C. Robinson University of Warwick Warwick, England, UK Prof. O.P. Kuipers University of Groningen Haren, Netherlands Dr M. Kolkman Genencor International BV Leiden, Netherlands Prof. Dr M. Müller Universitätsklinikum Freiburg Freiburg, Germany Prof. T. Palmer University of Dundee Dundee, Scotland, UK Dr L. F. Wu Laboratoire de Chimie Bactérienne (LCB) UPR9043, CNRS Marseille, France Prof. Dr M. Hecker Ernst-Moritz-Arndt-Universitaet Greifswald Greifswald, Germany Prof. Dr W. Kühlbrandt and Dr K. Model Max-Planck Institute of Biophysics Frankfurt am Main, Germany Prof. S. Iwata and Dr L. Carpenter Imperial College of Science, Technology and Medicine London, England, UK Prof. Dr R. Freudl Forschungszentrum Jülich GmbH Jülich, Germany TB Treatment Marker | 105 Establishing a TB treatment efficacy marker http://www.treaTBest.com

BACKGROUND with active TB, and carries a prognostic The focus of the TB Treatment Marker value during the treatment period, as project was on investigating the possibility well as whether suPAR levels decrease of creating a novel approach to moni- in patients that respond to therapy. tor tuberculosis (TB) treatment efficacy, which would lead to a more rational use EXPECTED RESULTS of drugs, and reduce the incidences An analysis of treatment efficacy and of resistance to TB medication. mortality in TB suspects and during the TB treatment programme were Since the war in the 1990s in Guinea carried out at the end of 2007. Bissau, laboratory facilities for diag- nosing TB have been inadequate. As Potential applications: part of the project, the consortium A simple laboratory analysis that can built a functional TB laboratory. reduce mortality and shed light on TB treatment efficacy can have a major Of some 2 000 screened TB sus- influence on the lifetime expectancy and pects, 400 diagnosed with active TB quality of life of people in Guinea Bis- were included in the study by De- sau and in all areas of the world where cember 2006 and an 8-month treat- TB and HIV (human immunodeficiency ment follow-up was carried out. virus) cause despair and mortality.

Problem: Project Coordinator No method to successfully monitor the effi- Dr Jesper Eugen-Olsen cacy of TB treatment currently exists. Upon ViroGates A/S Scion-DTU diagnosis, patients are treated for TB with a Diplomvej 377 course of medication lasting approximately 2800 Kgs. Lyngby, Denmark Tel. +45 88708258 six to nine months. If the primary treatment Fax +45 88708090 fails, a stringent and time-consuming analy- E-mail: [email protected] sis is made to select appropriate and effective antibiotics as a second-line treatment. Partners Ian Laquian Mortality is high in both TB suspects and ViroGates A/S Kgs. Lyngby, Denmark in TB patients during treatment, and simple and inexpensive methods for identify- Dr Peter Aaby The Bandim Health Project ing individuals at risk are warranted. Copenhagen, Denmark Dr Paulo Rabna AIMS Bissau, Guinea-Bissau TB Treatment Marker aimed to deter- Guinea-Bissau mine whether the blood plasma protein Dr Christian Wejse suPAR (soluble urokinase Plasminogen Danish Medical Assocation Copenhagen, Denmark Activator Receptor) is elevated in patients

 Project number: LSSP-CT-2005-012173  EC contribution: €375 104  Duration: 24 months + 12 months extension  Type: Specific Support Action  Starting date: 1 January 2005 106 | TB-DRUG OLIGOCOLOR Development of a molecular platform for the simultaneous detection of Mycobacterium tuberculosis resistance to rifampicin and fluoroquinolones http://www.projektrum.net/~oligocolor

BACKGROUND integration into a single solid support Treatment success and containment of of the capacity to detect resistance drug-resistant tuberculosis (TB) rely on to fluoroquinolone and confirm the a timely laboratory diagnosis. In view of identification of M. tuberculosis. this, a versatile and user-friendly molecular platform was proposed for the identifica- Potential applications: tion of Mycobacterium tuberculosis in The analysis of genes involved in the resist- clinical specimens and the simultaneous ance to key anti-TB agents will enhance detection of resistance to two key anti-TB the understanding of microbial genetic agents: rifampicin and fluoroquinolones. events leading to TB treatment failure. Additionally, mutated gene sequences will Problem: become available for eventual use in drug The management and control of multidrug target research and tool development. resistant tuberculosis (MDRTB) relies on solid laboratory support. The spread of MDRTB Project Coordinator can be prevented only if patients with drug- Prof. Françoise Portaels resistant disease are detected and treated Mycobacteriology Unit Prince Leopold Institute of Tropical Medicine with a combination of effective drugs. Nationalestraat 155 2000 Antwerp, Belgium AIMS Tel. +32 32476317 TB-DRUG OLIGOCOLOR targeted the de- Fax +32 32476333 E-mail: [email protected] velopment of a modification of the DIAPOPS technique (detection of the immobilised Partners amplified product in one phase system) Dr Dick Van Soolingen for the early detection of resistance to National Institute for Public Health rifampicin in M. tuberculosis, as well as the and the Environment detection of resistance to fluoroquinolones. Bilthoven, Netherlands It also aimed to perform a small preclinical Dr. Sven Hoffner evaluation in three laboratories to evalu- Swedish Institute for Infectious Disease Control Solna, Sweden ate the combined platform directly using clinical samples and early liquid cultures. Patricia Del Portillo Corporación CorpoGen Bogotá, Colombia EXPECTED RESULTS Dr. Viviana Ritacco TB-DRUG OLIGOCOLOR antici- INEI-ANLIS ‘Carlos G. Malbrán’ pated the following results: Buenos Aires, Argentina

Nora Morcillo development of a molecular tool Hospital Zonal Especializado for the rapid detection of rifampicin de Agudos y Cronicos resistance in M. tuberculosis di- Dr. Cetrángolo rectly from clinical samples; Vicente Lopez (Buenos Aires), Argentina

 Project number: LSHP-CT-2004-516028  EC contribution: €768 856  Duration: 33 months  Type: Specific Targeted Research Project  Starting date: 1 January 2005 TRAINAU | 107

Training risk assessment in non-human antimicrobial usage http://www.trainau.dk

BACKGROUND AIMS TRAINAU is a multidisciplinary Early Stage TRAINAU’s objectives are to answer the Training site on identification, characteri- following main questions in order to assess sation and assessment of public health the risks of non-human antimicrobial usage: risks associated with non-human use antimicrobials. The international dimen- To which extent do different pat- sion of TRAINAU is ensured through terns of antimicrobial drug use the strong networks of the host group select for the occurrence of re- with European universities, research sistant bacteria in animals? institutions as well as with international By which routes and at what rates do organisations. Fellows will establish links resistant bacteria and resistance genes across Europe, stimulating future inter- transmit from animals to humans? national collaborations and producing What is the current and potential positive effects on their future careers. future public health impact of resistant bacteria and resistance de- TRAINAU contributes to coordination of terminants from food animals? research training in the area of microbiological risk assessment and enables EXPECTED dissemination of principles and methods AND OBTAINED RESULTS for surveillance of antimicrobial us- The research activities have generated age and resistance to other European data and developed new methods in order countries. TRAINAU also contributes to answer questions that are of crucial to reinforce the capacity of emerging importance for conducting risk-based research groups through enhancing the evaluations. The research activities have scientific capacities of the fellows. been focused on specific antimicrobial classes used in animals and the prelimi- Problem: nary results are very promising, and by Non-human use of antimicrobials, in far exceed the expected outcome. particular the use in food animals, contributes to the public health problems in The epidemiological relationships between relation to antimicrobial resistant human bacterial isolates from animals, food, infections. Control efforts should be and humans have been determined by guided by microbial risk assessment in molecular methods. Resistance genes and an integrated food chain perspective. the associated mobile genetic elements have been characterised and horizontal transfer between animal and human bacterial populations have been investigated.

 Project number: MEST-CT-2004-007819  EC contribution: €1 582 182  Duration: 48 months  Type: Marie Curie – Early Stage Training  Starting date: 1 April 2005 108 | TRAINAU

The project’s fellows are collaborating on a quantitative risk assessment using their obtained results and the present literature; the outcome of this assessment looks promising but is still under further preparation. A full list of publications directly related to the programme is also available on the website.

Potential applications: The Early Stage Training programme will strive to continue the activities in a postdoc-based EU research programme.

Project Coordinator Prof. Henrik C. Wegener University of Copenhagen Faculty of Life Sciences Bülowsvej 17 1870 Frederiksberg C, Denmark E-mail: [email protected] Partners Prof. Frank Aarestrup Technical University of Denmark Søborg, Denmark Prof. Bent Halling-Sørensen University of Copenhagen Copenhagen, Denmark Dr Anette Hammerum Statens Serum Institut Copenhagen S, Denmark TRIoH | 109

Targeting replication and integration of HIV http://www.kuleuven.be/molvirgen/projects/trioh/indextr.htm

BACKGROUND Potential applications: TRIoH developed several novel compounds Scientific publications in peer- targeting HIV entry, nucleocapsid, RT reviewed journals and presenta- or integrase. The discovery of LEDGF/ tions at international meetings; p75 as a major novel target for HIV drug A website for communication with the discovery is one of the most exciting scientific community and general public; new directions in HIV molecular virology An initiative towards AIDS in originating from TRIoH in recent years. developing countries; This work has received international ap- The creation of t praisal and offers excellent options for The TRIoH training programme was economic valorisation in the near future. established to organized practical trainings, theoretical classes and a AIMS yearly symposium for young research- The general objective was to integrate the ers within TRIoH and African and Indian various research efforts from different Euro- students, including the funding of a pean partners on novel anti-HIV molecules young researcher special award. targeting viral replication and integration. Project Coordinator OBTAINED RESULTS Prof. Myriam Witvrouw The results obtained by TRI- Katholieke Universiteit Leuven Molecular Medicine oH include the following. Oude Markt 13 3000 Leuven, Belgium Tel. +32 16322170 Optimisation and use of a multi- Fax +32 16322131 parametric assay for entry/fusion was E-mail: [email protected] successful to identify new compounds against virus attachment, interac- Partners tion with CD4, HIV co-receptors, Dr. Zeger Debyser gp41-dependent fusion and HIV- Katholieke Universiteit Leuven Leuven, Belgium envelope-induced cell-death. Optimisation and use of new NC assays Dr. José A. Esté have been successful in identifying Fundació irsiCaixa compounds with anti-NC activity in Badalona, Spain vitro. Some hits show anti-HIV activity Dr. Jean-Luc Darlix in a multiple round replication assay. INSERM – ENS Lyon, France Dr. Jaume Vilarrasa Universitat Barcelona Barcelona, Spain

 Project number: LSHB-CT-2003-503480  EC contribution: €11 610 500  Duration: 36 months + 6 months extension  Type: Specific Targeted Research Project  Starting date: 1 January 2004 110 | TRIoH

Dr. Tobias Restle Dr. Richard Benarous Universitätsklinikum Schleswig-Holstein INSERM, Institut Cochin Lübeck, Germany Paris, France Prof. Alba Chimirri Dr. Inmaculada Robina Università degli Studi di Messina Universidad de Sevilla Messina, Italy Seville, Spain Dr. Ursula Dietrich Dr. Veljko Veljkovic Georg-Speyer-Haus Institute of Nuclear Sciences Frankfurt am Main, Germany Belgrade, Serbia Dr. Gilles Divita Dr. José Villalain CNRS Molecular and Cellular Biology Institute Montpellier, France Elche-Alicante, Spain Dr. Joachim Engels Dr. Pierre Vogel Johann Wolfgang Goethe-Universität École Polytechnique Féderale de Lausanne Frankfurt, Germany Lausanne, Switzerland Marina Gottikh Dr. Nils Gunnar Johansson Moscow State University Medivir AB Moscow, Russia Huddinge, Sweden Dr. Nicola M. Howarth Dr. Jean-Christophe Rain Heriot-Watt University Hybrigenics SA Edinburgh, Scotland, UK Paris, France Dr. Robert Kaptein Dr. Hans Langedijk Utrecht University Pepscan Holding NV Utrecht, Netherlands Lelystad, Netherlands Dr. Oliver Keppler University of Heidelberg Heidelberg, Germany Dr. Lajos Kovacs University of Szeged Szeged, Hungary Dr. Giovanni Maga Istituto di Genetica Moleculare – CNR Pavia, Italy Dr. Silvio Massa Università degli Studi di Siena Siena, Italy Dr. Yves Mély Université Louis Pasteur Strasbourg Strasbourg, France Dr. Jean-François Mouscadet École Normale Supérieure de Cachan Paris, France Tuberculosis China | 111 The diversity of Mycobacterium tuberculosis strains in China: tracing the origins of the worldwide dispersion of the multidrug-resistant Beijing genotype http://www.u-psud.fr/

BACKGROUND antigenic characteristics and develop a In China, a large fraction of the population new protective vaccine, and to under- is infected by Mycobacterium tuberculosis stand how MTB strains vary and adapt to (MTB), the bacteria responsible for tuber- new treatments or vaccines. This was an culosis (TB), with 500 000 new cases re- ambitious project necessitating serious ported each year. A significant proportion of organisation and a long-term follow-up. strains is resistant to multiple drugs used to treat this disease. The attenuated Mycobac- OBTAINED RESULTS terium bovis Bacillus Calmette Guerin (BCG) The consortium obtained is the only available vaccine against TB, but the following results: it does not provide consistent protection. genetic diversity of MTB strains, Tuberculosis China investigated MTB allowing a description of promi- genetic diversity in China (analysis of nent bacterial families and their 6 000 strains from 31 provinces). The distribution in China (Figure 1); goal was to characterise the dominant role of BCG vaccination in emer- bacterial populations in China and to gence of new TB strains; ascertain whether the dispersion of multidrug-resistance (MDR) strains, the Beijing type is of clonal origin. potentially triggered by the inadequate use of antibiotics. This work was the subject of Wan Kang- lin’s PhD thesis (Université Paris-Sud, 8 Potential applications: October 2008) under the co-supervision Studies are being performed in Beijing of Dr G. Vergnaud and Prof. Xu Jianguo. to identify MTB antigens and epitopes for new protective vaccines and specific Problem: diagnostic reagents. Immunogenicity and A third of the world’s population, mostly in protective capacity may be increased by poor countries, is currently latently infected adding to the BCG strains antigens that by MTB. The extensive use of the BCG induce a T-cell response (Pym et al., 2003). vaccine has not led to eradication of this Project Coordinator disease; on the contrary, it may have al- Dr. Christine Pourcel lowed some strains to emerge, especially in GPMS, Institut de Génétique et Microbiologie, countries where the use of drugs was inad- Bât 400, Université Paris Sud-XI equate. In China, a particular strain family 91405 Orsay Cedex France called the ‘Beijing family’ has been found to Tel: +33 1 69 15 30 01 predominate (van Soolingen et al., 1995). Fax: +33 1 69 15 66 78 E-mail: [email protected] AIMS Partners The objectives of the Tuberculosis China Dr. Dick van Soolingen National Institute project were to help identify emerging of Public Health and the Environment MTB strains in order to determine their The Netherlands

 Project number: 012166  EC contribution: €150 000  Duration: 24 months  Type: Specific Support Action  Starting date: 1 December 2005 112 | UNITE-MORE

Uniformity in testing and monitoring HIV resistance

BACKGROUND including standardised laboratory proce- Antiretroviral drugs are increasingly be- dures and quality assurance programmes. ing provided to patients living with the human immunodeficiency virus (HIV) in EXPECTED RESULTS developing countries. Experience gained support of the establishment of a uni- in Europe and North America has shown form global network for HIV drug re- that the use of these drugs dramatically sistance surveillance, UNITE-MORE reduced mortality but is also associated standardised laboratory procedures with the emergence of drug-resistant HIV. and quality assurance programmes.

The EU-funded ‘Strategy to Control UNITE-MORE will act as a key force in Spread of HIV Drug Resistance’ (SPREAD) global efforts on HIV drug resistance network gained a leading role in the surveillance using existing European area of surveillance of HIV drug resist- activities under SPREAD, and the WHO ance. Within UNITE-MORE, SPREAD Global HIV Drug Resistance programme closely cooperated with the World Health within the ‘3 by 5 initiative’ as a strong and Organization (WHO) to support the es- solid basis. In addition, UNITE-MORE will tablishment of a uniform global network contribute to the dissemination of knowl- for HIV drug resistance surveillance. edge across countries in four continents.

UNITE-MORE actively contributed to Potential applications: the further development, transfer and The surveillance network could provide take-up of the SPREAD clinical labora- governments, scientists and policymak- tory guidelines and systems at global ers with relevant and comparable global level. It also contributed to the objec- data on the prevalence, transmission and tives of the European Research Area trends of HIV drug resistance. It could (ERA), increased networking at glo- provide a resource for addressing key bal level and raising the scientific and questions of HIV drug-resistance patterns technological profile of Europe. and spread related to HIV genetic diversity.

Problem: Project Coordinator If the further spread of HIV drug re- Dr Charles A. B. Boucher sistance is not controlled, the fight University Medical Center Utrecht Department of Virology G04-614 against the aquired immune defi- Heidelberglaan 100 ciency syndrome (AIDS) pandemic 3584 CX Utrecht, Netherlands Tel. + 31 302506526 could be seriously hampered. Fax + 31 302505426 E-mail: [email protected] AIMS Partners UNITE-MORE aimed to support the Dr David Sutherland establishment of a uniform global net- World Health Organization work for HIV drug resistance surveillance, Geneva, Switzerland

 Project number: LSHP-CT-2004-516030  EC contribution: €375 000  Duration: 24 months  Type: Specific Support Action  Starting date: 1 January 2005 VIRGIL | 113 European vigilance network for the management of antiviral drug resistance http://www.virgil-net.org

BACKGROUND for the Study of the Liver), these results VIRGIL was the first European surveillance could be adopted by health authorities for network capable of addressing current the establishment of official guidelines. and emerging antiviral drugs resistance developments in the field of influenza and In the case of hepatitis C, several in vitro viral hepatitis. VIRGIL sought to integrate studies identified synergies and antago- the fragmented European capacities nisms between antiviral molecules, new and major expertise in the field into a more effective interferons, as well as single coherent Network of Excellence. new viral targets for treatments.

Problem: A number of standardised criteria for The high frequency of drug resistance, data collection in clinical trials have been which may be due to the patient (host), the established allowing for a comparison of virus or a combination of both, is a conse- the results obtained in various trials. quence of the successful development of new antiviral therapies in recent decades. Several clinical trials have been initiated on these databases by VIRGIL to AIMS characterise resistances of HBV to new The primary goal was to gradually molecules such as entecavir or tenofovir, integrate resources and skills dispersed and resistances of HCV to dual therapy throughout Europe to achieve com- with peg-interferon and ribavirin. mon research objectives, including the study of the socioeconomic dimen- VIRGIL plans to develop centralised clinical sion of antiviral drug resistance. trial services with major pharmaceutical groups and promote the integration of SMEs EXPECTED (biotechs) in the European economic tissue AND OBTAINED RESULTS by linking them with various regions of ex- The preliminary results obtained on antiviral cellence represented by VIRGIL’s partners. drugs used to treat influenza and hepatitis B and C demonstrate the pioneer role in Potential applications: Europe of an integrated approach link- The skills and infrastructures developed ing basic research and clinical research. in the context of this programme could be mobilised in the event of an influenza VIRGIL teams were the first to precisely pandemic. All EU Member States have characterise resistances to newly marketed existing stocks of oseltamivir. These drugs antiviral drugs (adefovir, entecavir and will only be useful if they are used ration- multi resistant strains) for the treatment of ally, and if the emergence of resistant hepatitis B. As a result of the links forged viral strains is controlled by continuous between VIRGIL and scientific societies surveillance set up throughout the EU ac- such as EASL (European Association cording to a sufficiently dense network.

 Project number: LSHM-CT-2004-503359  EC contribution: €9 000 000  Duration: 48 months  Type: Network of Excellence  Starting date: 1 May 2004 114 | VIRGIL

Project Coordinator Dr. Jean-Marie Cohen Prof. Fabien Zoulim Réseaux d’Observation des Maladies et des INSERM Unit 271 and Liver Dept. Epidémies (OPEN ROME) Institut Universitaire de France Paris, France 151 Cours Albert Thomas Dr. Solko Schalm 69003 Lyon, France Erasmus Medical Centre Rotterdam Tel. + 33 4 72 68 19 71 Rotterdam, Netherlands E-mail: [email protected] Dr. Alfredo Alberti Project Manager Venetian Institute of Molecular Medicine Padova, Italy Dr Jerome Weinbach Inserm-Transfert Dr. Rafaele Esteban Mur and Dr. Maria Buti 7 Rue Watt Hospital Universitario Valle Hebron 75 013 Paris, France Barcelona, Spain Tel. +33 1 55 03 01 39 Dr. Xavier Forns and Dr. Jordi Bruix E-mail: [email protected] Hospital Clinic Provincial de Barcelona Partners Barcelona, Spain Prof. Christian Trepo and Dr Georgios Germanidis Prof. Christian Brechot Papageorgiou General Hospital INSERM Thessalonica, Greece Lyon, France Dr. David Mutimer Prof. Bruno Lina The University of Birmingham Université Claude Bernard Lyon 1 Birmingham, England, UK Lyon, France Dr. Francesco Negro Prof. Michael Manns Université de Genève Medizinische Hochschule Hannover Geneva, Switzerland Hannover, Germany Dr. Krzysztof Bielawski Prof. Jean-Michel Pawlotsky University of Gdansk Université Paris XII-Val-de-Marne Gdansk, Poland Paris, France Prof. Etienne Sokal Dr. Maria Zambon and Dr. Pat Cane Université Catholique de Louvain Louvain, Belgium Health Protection Agency - Central Public Health Laboratory Dr. Vincente Soriano London, England, UK AEIS-Hospital Carlos III Madrid, Spain Prof. Ralf Bartenschlager Universitätsklinikum Heidelberg Prof. Howard Thomas Heidelberg, Germany and Dr. Peter Karayiannis Imperial College of Science, Dr. Alan Hay Technology and Medicine British Medical Research Council London, England, UK London, England, UK Prof. Stefan Zeuzem Dr. Gerd Pape, Dr. Helmut Diepolder, Universität des Saarlandes Dr. Thomas Mueller Saarbrücken, Germany Ludwig Maximilians Universität München Munich, Germany Dr. Isabella Donatelli Istituto Superiore di Sanità Dr. Johannes Bode Rome, Italy Universitätsklinikum Düsseldorf Düsseldorf, Germany Prof. Sylvie van der Werf Institut Pasteur Dr. Johan Neyts Paris, France Katholieke Universiteit Leuven Leuven, Belgium Dr. Oliver Planz Federal Research Centre Prof. Willy Spaan for Virus Diseases of Animals Leiden University Medical Center Tubingen Leiden, Netherlands Germany Prof. John Oxford Dr. Hans Dieter Klenk and Wolfgang Garten Retroscreen Virology Ltd Philipps-Universität Marburg London, England, UK Marburg, Germany VIRGIL | 115

Dr. Juna Ortin Dr. Gerhard Puerstinger Consejo Superior de Investigaciones Cientificas University of Innsbruck Madrid, Spain Innsbruck, Austria Dr. Robertus Ruigrok Dr. Gilles Avenard Université Joseph Fourier, Grenoble I BioAlliance Pharma SA Grenoble, France Paris, France Dr. Hubert Blum, Dr. Thomas Baumert, Dr. Guy Vernet and Dr. Glaucia Baccala Dr. Michael Nasal, Dr. Darius Moradpour bioMérieux SA Universitätsklinikum Freiburg Marcy l’Etoile, France Freiburg, Germany Prof. Avidan Neumann Uppsala University Bar-Ilan University Helena Danielson Ramat Gan, Israel Uppsala, Sweden Dr. Bryan Grenfell and Dr. Derek Smith Prof. Luca Guidotti Chancellor, Masters and Scholars Fondazione Centro San Raffaele Del Monte Tabor of the University of Cambridge Milan, Italy Cambridge, England, UK Prof. Joerg Petersen Dr. John Paget Universitätsklinikum Hamburg – Eppendorf Hamburg, Germany Netherlands Institute for Health Services Research Dr. Stéphane Bressanelli and Dr. Gilbert Utrecht, Netherlands Deléage Centre National Dr. Jerome Weinbach de la Recherche Scientifique (CNRS) Inserm-Transfert SA Paris, France Paris, France Dr. Nicole Zitzmann and Dr. Paul Klenerman Dr. Massimo Levrero Chancellor, Masters and Scholars Fondazione Andrea Cesalpino of the University of Oxford Arezzo, Italy Oxford, England, UK Dr. Stephan Ludwig Dr. Stephan Pleschka University of Muenster Justus-Liebig-Universitaet-Giessen Muenster, Germany Giessen, Germany Mr. Evert-Ben Van Veen Dr. Thorsten Wolff MedlawConsult Robert Koch-Institute The Hague, Netherlands Berlin, Germany Prof. Graham Foster Dr. Carlo Ferrari and Dr. Gabriele Missale Queen Mary and Westfield College Azienda Ospedaliera di Parma London, England, UK Parma, Italy Dr. Jean-Claude Schmit Dr. Thomas Berg Centre de Recherche Public-Santé du Universitätsklinikum Berlin Luxembourg Berlin, Germany Val Fleuri, Luxembourg Dr. Matti Saellberg and Dr. Ola Weiland Dr. Christian Trautwein Karolinska Institute University of Aachen Solna, Sweden Aachen, Denmark Dr. Mark Thursz Riotech Pharmaceuticals Ltd VIRGIL associate members: London, England, UK Russia, Cyprus and Turkey Dr. Guiseppe Pastore and Dr. Teresa Santantonio Prof. Vladimir Chulanov University of Bari Center for Molecular Diagnostics Bari, Italy Moscow, Russia Dr. Juerg Reichen and Dr. Andreas Cerny Prof. Selim Badur University of Bern İstanbul Üniversitesi Bern, Switzerland Istanbul, Turkey Dr. Anders Vahlne Prof. Leondios G. Kostrikis Tripep AB University of Cyprus Huddinge, Sweden Nicosia, Cyprus 116 | VIROLAB

A virtual lab for decision support in viral diseases treatment

http://www.virolab.org

BACKGROUND Project Coordinator ViroLab offers a unique opportunity as a Prof. Peter Sloot blueprint for the many potential diseases University of Amsterdam Kruislaan 403 where genetic information will become 1098 SJ Amsterdam, Netherlands important in future years. The virtual labo- Tel. +31 205257537 ratory supports tools for statistical analysis, Fax +31 205257419 E-mail: [email protected] visualisation, modelling and simulation to predict the temporal virological and Partners immunological response of viruses with Prof. Charles Boucher complex mutation patterns to drug therapy. and Dr David van de Vijver University Medical Center Utrecht Utrecht, Netherlands AIMS The main objectives of ViroLab included: Dipl. Ing. Stefan Wesner High Performance Computing Center Stuttgart Stüttgart, Germany a virtual organisation that binds the Dr Andrea de Luca various components of ViroLab; Institute of Clinical Infectious Diseases, a virtual laboratory infrastructure Catholic University Rome, Italy for transparent workflow, data access, experimental execution Dr Lidia Ruiz Badalona Institute de recerca de la SIDA and collaboration support; Barcelona, Spain epidemiological validation and dis- Dr Carlo Torti semination of results to stakeholders. University of Brescia Brescia, Italy EXPECTED RESULTS Prof. Anne-Mieke Vandamme The collaborative research will result in a Catholic University Leuven virtual laboratory for decision support in in- Leuven, Belgium fectious diseases treatment. New, valuable Dr Viktor Müller clinical data and information on treatment Eötvös Loránd University ELTE Budapest, Hungary of HIV-infected persons will emerge, providing essential insights into the prevalence of Pawel Plaszczak GridwiseTech SP.z.o.o drug resistance patterns in treated individu- Krakow, Poland als on a continuous basis. It is of crucial Dr Marian Bubak importance for future development of new University of Science and Technology drugs effective against drug-resistant HIV. Institute of Computer Science and Academic Computer Centre CYFRONET Krakow, Poland Potential applications: ViroLab will reliably predict drug suscepti- Prof. Peter Coveney University College London bility and virological response, and provide London, England, UK researchers with a support environment to Dr Wilco Keulen study trends at HIV resistance on individual Virology Education BV and population (epidemiological) levels. Utrecht, Netherlands

 Project number: 027446  EC contribution: €3 334 840  Duration: 36 months  Type: Specific Targeted Research Project  Starting date: 1 March 2006 VITBIOMAL | 117

Vitamin biosynthesis as a target for antimalarial therapy http://www.hyg.uni-heidelberg.de/vitbiomal

BACKGROUND development of P. falciparum blood Plasmodium falciparum infections place stage forms, indicating that vitamin a tremendous burden on global health, B6 biosynthesis is sufficient to cover which is becoming increasingly aggravated the needs of pyridoxal 5-phosphate; by the worrying rise in P. falciparum drug determination of structures: Pdx2 resistance, making the discovery of novel from P. falciparum (1.6 Å), Pdx1 from intervention strategies imperative. The Bacillus subtilis (to 2.0 Å), Pdx2 from VITBIOMAL project explored the inhibition B. subtilis in free (1.7 Å) and inhibitor- of a recently identified parasite vitamin bio- complexed state (2.2 Å) and the ternary synthesis pathway as a therapeutic strategy complex of B. subtilis Pdx1:Pdx2 with and assessed its potential as drug target. substrate glutamine (2.1 Å) (3, 6); construction and testing of a homology Problem: model of the plasmodial PLP synthase. With 300–500 million clinical cases and 1–3 million deaths a year, malaria is Potential applications: one of the most fatal tropical diseases; The partners envision antimalarial there is an urgent need to develop and and possibly antiapicomplexan and/ pursue new therapeutic strategies. or antibacterial drug development.

AIMS Project Coordinator The aim of VITBIOMAL was to specifi- Dr Barbara Kappes cally assess vitamin B de novo biosyn- Universitätsklinikum Heidelberg 6 Abteilung Parasitologie thesis of Plasmodium as a target for Im Neuenheimer Feld 324 antimalarial drug development. 69120 Heidelberg, Germany Tel. +49 6221561774 Fax +49 6221564643 OBTAINED RESULTS E-mail: [email protected] The results obtained by VIT- BIOMAL include: Partners Prof. Sylke Müller generation of knockout parasites University of Glasgow Glasgow, Scotland, UK of the Pdx1 (vitamin B6 biosynthesis) and of the pdxK gene (vitamin Prof. Dr Teresa Fitzpatrick B6 uptake/salvage) in the mouse University of Zürich malaria model system; Zurich, Switzerland growth delay of the erythrocytic forms; Prof. Peter Macheroux Institute of Biochemistry massive reduction of sporozoite Graz, Austria numbers ranging from 90 (Pdx1 knockout) to 99% (pdxK knockout); Dr Ivo Tews Biochemie-Zentrum Heidelberg depletion of B6 vitamers from the der Universität Heidelberg (BZH) growth medium had no effect on the Heidelberg, Germany

 Project number: LSHP-CT-2005-012158  EC contribution: €1 000 000  Duration: 24 months  Type: Specific Targeted Research Project  Starting date: 1 June 2005 118 |

Index of Acronyms

A I ABS INTERNATIONAL 8 IPSE 71 ACE 10 L ACE-ART 12 ActinoGEN 14 LeishEpiNetSA 73 AMIS 16 M ANTIBIOTARGET 17 MagRSA 75 B MalariaPorin 76 BACELL HEALTH 19 MANASP 77 BURDEN 21 micro-MATRIX 78 MOSAR 79 C N CanTrain 22 CHAMP 24 NewHiv Targets 81 COBRA 25 NEWTBDRUGS 82 COMBIG-TOP 27 NM4TB 83 CombiGyrase 29 NPARI 85 CRAB 31 P D Phagevet-P 86 DRESP2 32 PNEUMOPEP 88 PREVIS 89 E R e-Bug 33 EACCAD 35 READ-UP 91 EAR 36 REBAVAC 92 EARSS 37 REPLACE 93 ERAPharm 39 S ESAC 41 SAFEWASTES 95 ESSTI 43 SavinMucoPath 96 ET-PA 45 SIGMAL 98 EU-IBIS 46 SLIC 100 EUCAST 49 StaphDynamics 101 EUR-INTAFAR 51 EURESFUN 53 T EuResist 55 Tat machine 103 Eurofungbase 57 TB Treatment Marker 105 EPG 59 TB-DRUG OLIGOCOLOR 106 EuropeHIVResistance 60 TRAINAU 107 EuroTB 62 TRIoH 109 Tuberculosis China 111 F FUNGWALL 64 U UNITE-MORE 112 G GENOSEPT 66 V GRACE 67 VIRGIL 113 VIROLAB 116 H VITBIOMAL 117 HAPPY AUDIT 69 | 119

Index of Coordinators

A L Prof. Dan I. Andersson (EAR) 36 Prof. Jean-Paul Latge (FUNGWALL) 64 Prof. Peter Andrew (PNEUMOPEP) 88 M Dr Joana Azeredo (Phagevet-P) 87 Dr Solomzi Makohliso (SLIC) 100 B Dr Nathalie Mathy (GENOSEPT) 66 Prof. Dr Eric Beitz (MalariaPorin) 76 Dr Didier Mazel (CRAB) 31 Prof. Julian Bion (GENOSEPT) 66 Dr Cliodna A.M. McNulty (e-Bug) 34 Dr Mike Birch (NPARI) 85 Prof. Michael A. Miles (LeishEpiNetSA) 73 Dr Lars Bjerrum (HAPPY AUDIT) 69 Prof. Lorenzo Morelli (ACE-ART) 13 Prof. Marc J. M. Bonten (ACE) 10 N Dr Charles A. B. Boucher (UNITE-MORE) 112 Prof. Birgitta Henriques Normark (PREVIS) 90 Prof. Dr Charles Boucher (EuropeHIVResistance) 60 Prof. Christian Brun-Buisson (MOSAR) 80 O C Dr. Marco R. Oggioni (DRESP2) 32 Prof. Miguel Cámara (ANTIBIOTARGET) 18 P Manny Chandra (EU-IBIS) 47 Dr. Serge Petit (READ-UP) 91 Prof. Stewart T. Cole (NM4TB) 84 Prof. Françoise Portaels D (TB-DRUG OLIGOCOLOR) 106 Dr. Christine Pourcel (Tuberculosis China) 111 Prof. Christian Doerig (SIGMAL) 99 Prof Gianni Pozzi (DRESP2) 32 Prof. Paul Dyson (ActinoGEN) 15 E R Mary Ramsay (EU-IBIS) 47 Prof. Hermann Einsele (MANASP) 77 Dr. Gian Maria Rossolini (DRESP2) 32 Dr Jesper Eugen-Olsen (TB Treatment Marker) 105 F S Prof. Dominique Sanglard (EURESFUN) 54 Prof. Jacques Fabry (IPSE) 71 Prof. Jacques Schrenzel (MagRSA) 75 Dr Dennis Falzon (EuroTB) 62 Dr. Olivier Schwartz (NewHiv Targets) 81 Mag. Annegret Frank (ABS INTERNATIONAL) 9 Dr. Mahavir Singh (NEWTBDRUGS) 82 Prof. Dr Uwe Frank (BURDEN) 21 Dr Jean Claude Sirard (SavinMucoPath) 97 Prof. Dr Chlodwig Franz (SAFEWASTES) 95 Prof. Peter Sloot (VIROLAB) 116 Prof. Jean-Marie Frère (EUR-INTAFAR) 52 Dr Jos van Strijp (AMIS) 16 G T Prof. Dr Roland Gareis (ABS INTERNTIONAL) 9 Dr Aldo Tagliabue (REBAVAC) 92 Prof. Herman Goossens (ESAC, Grace) 41, 68 Dr Edine W. Tiemersma (EARSS) 37 Prof. Laurent Gutmann (COBRA) 26 H V Prof. Cees A.M.J.J. van den Hondel Prof. Dr Jörg Hacker (EPG) 59 (Eurofungbase) 58 Prof. Colin Harwood (BACELL HEALTH) 20 Prof. Patrick Van Dijck (CanTrain) 23 Prof. Dr Lutz Heide (CombiGyrase) 30 Prof. Jan Maarten van Dijl I (StaphDynamics, Tat machine) 101, 103 Dr Francesca Incardona (EuResist) 56 Prof. Th.J.M. Verheij (CHAMP) 24 Prof. Cathy Ison (ESSTI) 43 Prof. Miguel Vicente (MATRIX) 78 K W Gunnar Kahlmeter (EUCAST) 50 Prof. R. John Wallace (REPLACE) 93 Dr Barbara Kappes (VITBIOMAL) 117 Prof. Henrik C. Wegener (TRAINAU) 108 Dr Thomas Knacker (ERAPharm) 39 Dr Rob J. L. Willems (ACE) 10 Christian Kuehne (ET-PA) 45 Prof. Myriam Witvrouw (TRIoH) 109 Dr. Ed J. Kuijper (EACCAD) 35 Prof. Dr Wolfgang Wohlleben (COMBIG-TOP) 28 Z Prof. Fabien Zoulim (VIRGIL) 114

European Commission

EU-funded FP6 Research Projects on Antimicrobial Drug Resistance

Luxembourg: Publications Office of the European Union

2010 — 124 pp. — 14.8 x 21.0 cm

ISBN 978-92-79-16745-4 doi:10.2777/22731

How to obtain EU publications

Free publications: • via EU Bookshop (http://bookshop.europa.eu); • at the European Commission’s representations or delegations. You can obtain their contact details on the Internet (http://ec.europa.eu) or by sending a fax to +352 2929-42758.

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Priced subscriptions (e.g. annual series of the Official Journal of the European Union and reports of cases before the Court of Justice of the European Union): • via one of the sales agents of the Publications Office of the European Union (http://publications.europa.eu/others/agents/index_en.htm). KI-30-10-483-EN-N doi:10.2777/22731 collaboration with the academic institutions. medium-sized enterprises working in close and participation a multitude of small of and information presented also shows the involvement and the expected outcome projects. of The challenges, the research goals addressed, (FP6). It provides an overview the of scientific funded under the Sixth Framework Programme about antimicrobial drug resistance projects The project catalogue contains information