DOCSLIB.ORG

Deciphering Antimycobacterial Activity of Cyclophostin/Cyclipostins

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Deciphering Antimycobacterial Activity of Cyclophostin/Cyclipostins THÈSE DE DOCTORAT DE L’UNIVERSITÉ D’AIX-MARSEILLE Soutenue par Phuong Chi NGUYEN Pour obtenir le grade de Docteur de l’Université d’Aix-Marseille Discipline: Biologie Spécialité: Microbiologie Deciphering antimycobacterial activity of Cyclophostin/Cyclipostins analogs and Oxadiazolones derivatives, two new promising family compounds in the treatment of tuberculosis and mycobacterial-related diseases Soutenue le 25 Mai 2018 devant le jury : Dr. Alain BAULARD (INSERM, Lille) Rapporteur Dr. Jean Denis PEDELACQ (IPBS, Toulouse) Rapporteur Dr. Véronique FONTAINE (ULB, Belgium) Examinatrice Pr. Sophie BLEVES (LISM, Marseille) Examinatrice-Présidente Dr. Céline CRAUSTE (IBMM, Montpellier) Examinatrice Dr. Stéphane CANAAN (LISM, Marseille) Directeur de thèse Acknowledgements I would like to take this opportunity to sincerely thank all people who have supported me during the time of my PhD. First and foremost, I offer the sincerest gratitude to my supervisor, Dr. Stéphane CANAAN. Thank you for your continuous support and guidance during the time I have spent in the group. I really appreciate your encouragement and excellent ideas whenever I was stuck. It has been 3 years since you offered me to come here. We have overcome many difficulties and now I am going to defense a good thesis. Thank you! Besides my supervisor, I would like to thank the rest of my thesis committee: Dr. Alain BAULARD and Dr. Jean Denis PEDELACQ, who have accepted to be reporters of this manuscript, Pr. Sophie BLEVÉS who has accepted as the president of the jury, Dr. Véronique FONTAINE and Dr. Céline CRAUSTE, for their acceptance as examiners. My sincere thanks goes to Dr. Jean-François CAVALIER, for advising me on the aspects of my work especially on biochemistry and chemistry. Thank you for your unwavering support during my time in the laboratory as well as be patient to correct all my manuscripts. I would take this opportunity to express my sincere gratitude to my wonderful colleagues. Thank you, Isabelle and Vanessa, for being kind and ready for help any time I need, despite of difference in language. Thanks Pierre for all your support through the time of my PhD with a lot of mini details have been discussed and solved to bring good results. Thanks Djalil for working together and produced two papers. I would also thank to two postdocs, Nabil and Ticiana, who shared their own knowledge, experiences and ideas. I also cannot thank enough to all Vietnamese students in Luminy and Marseille who make me feel at home even we live thousand miles away from our country. Thanks to brother Quan and sister Thuy for being so kind. I would also thank to French and foreigner students, I have had a great fortune of spending time with all of you. This acknowledgement would not be completed without mentioning endless love, support and encouragement from my husband and my family. Thank you for being always beside me and sharing all the joy and sorrow together. I am eternally thankful to my parents, my husband’s parents and my older brother. Thank you for your continuous encouragement. I am happy to have all beloved like you. Table of contents INTRODUCTION .................................................................................................................. 1 CHAPTER 1: General introduction ..................................................................................... 2 1.1. Tuberculosis, an overview ............................................................................................... 2 1.2. History timeline of Tuberculosis .................................................................................... 3 1.3. Diagnosis and vaccination ............................................................................................... 4 Diagnosis ................................................................................................................................... 4 Vaccines..................................................................................................................................... 5 1.4. Biological characteristics of M. tb .................................................................................. 6 General biology ......................................................................................................................... 6 Genome of M. tb ........................................................................................................................ 8 Cell envelope ............................................................................................................................. 9 1.5. Pathogenic life cycle ...................................................................................................... 12 Transmission ........................................................................................................................... 12 Initial infection ....................................................................................................................... 14 M. tb intracellular life ............................................................................................................. 14 Immune response to M. tb infection ........................................................................................ 14 Granulomas ............................................................................................................................. 15 1.6. Treatment of TB ............................................................................................................ 17 Standard treatment for TB ....................................................................................................... 17 Front-line drugs ...................................................................................................................... 17 1.7. Drug resistance and mechanisms .................................................................................. 21 1.8. Treatment in drug-resistance TB and new drugs development ................................. 23 Current treatment in drug-resistance TB ............................................................................... 24 New drugs in development ...................................................................................................... 25 1.9. Lipid metabolism of M. tb ............................................................................................. 26 CHAPTER II: Lipolytic enzymes in M. tb – the fundamental of a new drug family development .......................................................................................................................... 28 2.1. Serine hydrolase enzymes from M. tb: promising therapeutic targets ..................... 28 2.2. Mycobacterial lipolytic enzymes .................................................................................. 31 True lipases ............................................................................................................................. 32 Carboxylesterases ................................................................................................................... 35 Cutinases ................................................................................................................................ 37 Phospholipases ........................................................................................................................ 38 CHAPTER III: Inhibitors of lipolytic enzymes ................................................................. 40 3.1. Orlistat ............................................................................................................................ 40 3.2. Orlistat-core compounds .............................................................................................. 41 3.3. β-lactone EZ120 ............................................................................................................. 42 3.4. Lalistat ............................................................................................................................ 43 3.5. Oxadiazolone-core compounds .................................................................................... 45 3.6. Cyclophostin and Cyclipostins molecules .................................................................... 47 3.7. Activity-based protein profiling (ABPP), powerful chemical proteomic platform applied to investigate targets of CyC analogs and Oxadiazolones derivatives ............... 52 3.8. Objectives of my thesis .................................................................................................. 54 RESULTS .............................................................................................................................. 55 Article 1: Cyclipostins and Cyclophostin analogs as promising compounds in the fight against tuberculosis .............................................................................................................. 56 Article 2: Cyclophostin and Cyclipostins analogs, new promising molecules to treat mycobacterial-related diseases ............................................................................................ 84 Article 3: Cyclipostins and Cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo ........................................................ 93 Article 4: A biochemical and structural characterization of TesA a major thioesterase requires for PDIM and PGL syntheses in M. tuberculosis ............................................. 110 Article
Load more

Recommended publications
  • Efficacy and Safety of World Health Organization Group 5 Drugs for Multidrug-Resistant Tuberculosis Treatment
    ERJ Express. Published on September 17, 2015 as doi: 10.1183/13993003.00649-2015 REVIEW IN PRESS | CORRECTED PROOF Efficacy and safety of World Health Organization group 5 drugs for multidrug-resistant tuberculosis treatment Nicholas Winters1,2, Guillaume Butler-Laporte1 and Dick Menzies1,2 Affiliations: 1Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University, Montreal, PQ, Canada. 2Dept of Epidemiology and Biostatistics, McGill University, Montreal, PQ, Canada. Correspondence: Dick Menzies, Montreal Chest Institute, Room K1.24, 3650 St Urbain, Montreal, PQ, Canada, H2X 2P4. E-mail: [email protected] ABSTRACT The efficacy and toxicity of several drugs now used to treat multidrug-resistant tuberculosis (MDR-TB) have not been fully evaluated. We searched three databases for studies assessing efficacy in MDR-TB or safety during prolonged treatment of any mycobacterial infections, of drugs classified by the World Health Organization as having uncertain efficacy for MDR-TB (group 5). We included 83 out of 4002 studies identified. Evidence was inadequate for meropenem, imipenem and terizidone. For MDR-TB treatment, clarithromycin had no efficacy in two studies (risk difference (RD) −0.13, 95% CI −0.40–0.14) and amoxicillin–clavulanate had no efficacy in two other studies (RD 0.07, 95% CI −0.21–0.35). The largest number of studies described prolonged use for treatment of non- tuberculous mycobacteria. Azithromycin was not associated with excess serious adverse events (SAEs). Clarithromycin was not associated with excess SAEs in eight controlled trials in HIV-infected patients (RD 0.00, 95% CI −0.02–0.02), nor in six uncontrolled studies in HIV-uninfected patients, whereas six uncontrolled studies in HIV-infected patients clarithromycin caused substantial SAEs (proportion 0.20, 95% CI 0.12–0.27).
    [Show full text]
  • Clofazimine As a Treatment for Multidrug-Resistant Tuberculosis: a Review
    Scientia Pharmaceutica Review Clofazimine as a Treatment for Multidrug-Resistant Tuberculosis: A Review Rhea Veda Nugraha 1 , Vycke Yunivita 2 , Prayudi Santoso 3, Rob E. Aarnoutse 4 and Rovina Ruslami 2,* 1 Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia; [email protected] 2 Division of Pharmacology and Therapy, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia; [email protected] 3 Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran—Hasan Sadikin Hospital, Bandung 40161, Indonesia; [email protected] 4 Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6255HB Nijmegen, The Netherlands; [email protected] * Correspondence: [email protected] Abstract: Multidrug-resistant tuberculosis (MDR-TB) is an infectious disease caused by Mycobac- terium tuberculosis which is resistant to at least isoniazid and rifampicin. This disease is a worldwide threat and complicates the control of tuberculosis (TB). Long treatment duration, a combination of several drugs, and the adverse effects of these drugs are the factors that play a role in the poor outcomes of MDR-TB patients. There have been many studies with repurposed drugs to improve MDR-TB outcomes, including clofazimine. Clofazimine recently moved from group 5 to group B of drugs that are used to treat MDR-TB. This drug belongs to the riminophenazine class, which has lipophilic characteristics and was previously discovered to treat TB and approved for leprosy. This review discusses the role of clofazimine as a treatment component in patients with MDR-TB, and Citation: Nugraha, R.V.; Yunivita, V.; the drug’s properties.
    [Show full text]
  • The Antimycobacterial Activity of Hypericum Perforatum Herb and the Effects of Surfactants
    Utah State University DigitalCommons@USU All Graduate Theses and Dissertations Graduate Studies 8-2012 The Antimycobacterial Activity of Hypericum perforatum Herb and the Effects of Surfactants Shujie Shen Utah State University Follow this and additional works at: https://digitalcommons.usu.edu/etd Part of the Engineering Commons Recommended Citation Shen, Shujie, "The Antimycobacterial Activity of Hypericum perforatum Herb and the Effects of Surfactants" (2012). All Graduate Theses and Dissertations. 1322. https://digitalcommons.usu.edu/etd/1322 This Thesis is brought to you for free and open access by the Graduate Studies at DigitalCommons@USU. It has been accepted for inclusion in All Graduate Theses and Dissertations by an authorized administrator of DigitalCommons@USU. For more information, please contact [email protected]. i THE ANTIMYCOBACTERIAL ACTIVITY OF HYPERICUM PERFORATUM HERB AND THE EFFECTS OF SURFACTANTS by Shujie Shen A thesis submitted in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE in Biological Engineering Approved: Charles D. Miller, PhD Ronald C. Sims, PhD Major Professor Committee Member Marie K. Walsh, PhD Mark R. McLellan, PhD Committee Member Vice President for Research and Dean of the School of Graduate Studies UTAH STATE UNIVERSITY Logan, Utah 2012 ii Copyright © Shujie Shen 2012 All Rights Reserved iii ABSTRACT The Antimycobacterial Activity of Hypericum perforatum Herb and the Effects of Surfactants by Shujie Shen, Master of Science Utah State University, 2012 Major Professor: Dr. Charles D. Miller Department: Biological Engineering Due to the essential demands for novel anti-tuberculosis treatments for global tuberculosis control, this research investigated the antimycobacterial activity of Hypericum perforatum herb (commonly known as St.
    [Show full text]
  • Analysis of Mutations Leading to Para-Aminosalicylic Acid Resistance in Mycobacterium Tuberculosis
    www.nature.com/scientificreports OPEN Analysis of mutations leading to para-aminosalicylic acid resistance in Mycobacterium tuberculosis Received: 9 April 2019 Bharati Pandey1, Sonam Grover2, Jagdeep Kaur1 & Abhinav Grover3 Accepted: 31 July 2019 Thymidylate synthase A (ThyA) is the key enzyme involved in the folate pathway in Mycobacterium Published: xx xx xxxx tuberculosis. Mutation of key residues of ThyA enzyme which are involved in interaction with substrate 2′-deoxyuridine-5′-monophosphate (dUMP), cofactor 5,10-methylenetetrahydrofolate (MTHF), and catalytic site have caused para-aminosalicylic acid (PAS) resistance in TB patients. Focusing on R127L, L143P, C146R, L172P, A182P, and V261G mutations, including wild-type, we performed long molecular dynamics (MD) simulations in explicit solvent to investigate the molecular principles underlying PAS resistance due to missense mutations. We found that these mutations lead to (i) extensive changes in the dUMP and MTHF binding sites, (ii) weak interaction of ThyA enzyme with dUMP and MTHF by inducing conformational changes in the structure, (iii) loss of the hydrogen bond and other atomic interactions and (iv) enhanced movement of protein atoms indicated by principal component analysis (PCA). In this study, MD simulations framework has provided considerable insight into mutation induced conformational changes in the ThyA enzyme of Mycobacterium. Antimicrobial resistance (AMR) threatens the efective treatment of tuberculosis (TB) caused by the bacteria Mycobacterium tuberculosis (Mtb) and has become a serious threat to global public health1. In 2017, there were reports of 5,58000 new TB cases with resistance to rifampicin (frst line drug), of which 82% have developed multidrug-resistant tuberculosis (MDR-TB)2. AMR has been reported to be one of the top health threats globally, so there is an urgent need to proactively address the problem by identifying new drug targets and understanding the drug resistance mechanism3,4.
    [Show full text]
  • Revised Use-Function Classification (2007)
    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY IPCS INTOX Data Management System (INTOX DMS) Revised Use-Function Classification (2007) The Use-Function Classification is used in two places in the INTOX Data Management System: the Communication Record and the Agent/Product Record. The two records are linked: if there is an agent record for a Centre Agent that is the subject of a call, the appropriate Intended Use-Function can be selected automatically in the Communication Record. The Use-Function Classification is used when generating reports, both standard and customized, and for searching the case and agent databases. In particular, INTOX standard reports use the top level headings of the Intended Use-Functions that were selected for Centre Agents in the Communication Record (e.g. if an agent was classified as an Analgesic for Human Use in the Communication Record, it would be logged as a Pharmaceutical for Human Use in the report). The Use-Function classification is very important for ensuring harmonized data collection. In version 4.4 of the software, 5 new additions were made to the top levels of the classification provided with the system for the classification of organisms (items XIV to XVIII). This is a 'convenience' classification to facilitate searching of the Communications database. A taxonomic classification for organisms is provided within the INTOX DMS Agent Explorer. In May/June 2006 INTOX users were surveyed to find out whether they had made any changes to the Use-Function Classification. These changes were then discussed at the 4th and 5th Meetings of INTOX Users. Version 4.5 of the INTOX DMS includes the revised pesticides classification (shown in full below).
    [Show full text]
  • Terizidone.Pdf
    Essential Medicines List (EML) 2015 Application for the inclusion of terizidone in the WHO Model List of Essential Medicines, as reserve second‐line drugs for the treatment of multidrug‐resistant tuberculosis (complementary lists of anti‐tuberculosis drugs for use in adults and children) General items 1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of section 6.2.4 Antituberculosis medicines in the 2013 editions of both the WHO Model List of Essential Medicines (18th list) and the WHO Model List of Essential Medicines for Children (4th list)(1),(2). The proposal is to add terizidone to both the complementary list of anti‐tuberculosis medicines for adults and in children. Terizidone is not on the EML, but its sister medication, cycloserine, is on the complementary list in section 6.2.4 Antituberculosis medicines The applicant considers that terizidone should be viewed as an essential medicine for patients with multidrug‐resistant (MDR‐TB) and extensively drug‐resistant (XDR‐TB) disease. In many low resource settings, patients with these forms of tuberculosis are inadequately treated and often die because not enough medications are available to compose a suitable regimen (3). Second‐line drugs for the treatment of M/XDR‐TB are frequently not available; and global stock outs occur regularly. Terizidone should become more widely available to specialized care centres of national TB programmes and other health care providers treating M/XDR‐TB patients. The inclusion of terizidone as an anti‐tuberculosis agent on the EML will encourage pharmaceutical manufacturers to invest more in its production and will facilitate its inclusion in the national EML and its registration in countries where MDR and XDR‐TB are a health threat.
    [Show full text]
  • Antimycobacterial Natural Products – an Opportunity for the Colombian Biodiversity
    Review Juan Bueno1, Ericsson David Coy2, Antimycobacterial natural products – an Elena Stashenko3 opportunity for the Colombian biodiversity 1Grupo Micobacterias, Subdirección Red Nacional de Laboratorios, Instituto Nacional de Salud, Bogotá, D.C., Centro Colombiano de Investigación en Tuberculosis CCITB, Bogotá, Colombia. 2Laboratorio de Investigación en Productos Naturales Vegetales, Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Bogotá, Colombia. 3Laboratorio de Cromatografía, Centro de Investigación en Biomoléculas, CIBIMOL, CENIVAM, Universidad Industrial de Santander, Bucaramanga, Colombia. ABSTRACT centaje de los individuos afectados desarrollará clínicamente la enfermedad, cada año esta ocasiona aproximadamente ocho It is estimated that one-third part of the world population millones de nuevos casos y dos millones de muertes. Mycobac- is infected with the tubercle bacillus. While only a small per- terium tuberculosis es el agente infeccioso que produce la ma- centage of infected individuals will develop clinical tuberculo- yor mortalidad humana, comparado con cualquier otra especie sis, each year there are approximately eight million new cases microbiana. Los objetivos de los distintos programas para el and two million deaths. Mycobacterium tuberculosis is thus control de la tuberculosis son la cura y diagnóstico de la infec- responsible for more human mortality than any other single ción activa, la prevención de recaídas, la reducción de trans- microbial species. The goals of tuberculosis control are focused misión y evitar la aparición de la resistencia a los medicamen- to cure active disease, prevent relapse, reduce transmission tos. Por más de 50 años, los productos naturales han sido útiles and avert the emergence of drug-resistance. For over 50 years, en combatir bacterias y hongos patógenos.
    [Show full text]
  • Against the Plasmodium Falciparum Apicoplast
    A Systematic In Silico Search for Target Similarity Identifies Several Approved Drugs with Potential Activity against the Plasmodium falciparum Apicoplast Nadlla Alves Bispo1, Richard Culleton2, Lourival Almeida Silva1, Pedro Cravo1,3* 1 Instituto de Patologia Tropical e Sau´de Pu´blica/Universidade Federal de Goia´s/Goiaˆnia, Brazil, 2 Malaria Unit/Institute of Tropical Medicine (NEKKEN)/Nagasaki University/ Nagasaki, Japan, 3 Centro de Mala´ria e Doenc¸as Tropicais.LA/IHMT/Universidade Nova de Lisboa/Lisboa, Portugal Abstract Most of the drugs in use against Plasmodium falciparum share similar modes of action and, consequently, there is a need to identify alternative potential drug targets. Here, we focus on the apicoplast, a malarial plastid-like organelle of algal source which evolved through secondary endosymbiosis. We undertake a systematic in silico target-based identification approach for detecting drugs already approved for clinical use in humans that may be able to interfere with the P. falciparum apicoplast. The P. falciparum genome database GeneDB was used to compile a list of <600 proteins containing apicoplast signal peptides. Each of these proteins was treated as a potential drug target and its predicted sequence was used to interrogate three different freely available databases (Therapeutic Target Database, DrugBank and STITCH3.1) that provide synoptic data on drugs and their primary or putative drug targets. We were able to identify several drugs that are expected to interact with forty-seven (47) peptides predicted to be involved in the biology of the P. falciparum apicoplast. Fifteen (15) of these putative targets are predicted to have affinity to drugs that are already approved for clinical use but have never been evaluated against malaria parasites.
    [Show full text]
  • 1, 4-Dihydropyridine Calcium Channel Blockers: Homology Modeling Of
    Hindawi Publishing Corporation ISRN Medicinal Chemistry Volume 2014, Article ID 203518, 14 pages http://dx.doi.org/10.1155/2014/203518 Research Article 1,4-Dihydropyridine Calcium Channel Blockers: Homology Modeling of the Receptor and Assessment of Structure Activity Relationship Moataz A. Shaldam, Mervat H. Elhamamsy, Eman A. Esmat, and Tarek F. El-Moselhy Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt Correspondence should be addressed to Tarek F. El-Moselhy; [email protected] Received 28 September 2013; Accepted 5 December 2013; Published 10 February 2014 Academic Editors: R. B. de Alencastro, P. L. Kotian, O. A. Santos-Filho, L. Soulere,` and S. Srichairatanakool Copyright © 2014 Moataz A. Shaldam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. +2 1,4-Dihydropyridine (DHP), an important class of calcium antagonist, inhibits the influx of extracellular Ca through L-type voltage-dependent calcium channels. Three-dimensional (3D) structure of calcium channel as a receptor for 1,4-dihydropyridine is a step in understanding its mode of action. Protein structure prediction and modeling tools are becoming integral parts of the standard toolkit in biological and biomedical research. So, homology modeling (HM) of calcium channel alpha-1C subunit as DHP receptor model was achieved. The 3D structure of potassium channel was used as template for HM process. The resulted dihydropyridine receptor model was checked by different means to assure stereochemical quality and structural integrity of the model.
    [Show full text]
  • SDC 1. Supplementary Notes to Methods Settings Groote Schuur
    Mouton JP, Njuguna C, Kramer N, Stewart A, Mehta U, Blockman M, et al. Adverse drug reactions causing admission to medical wards: a cross-sectional survey at four hospitals in South Africa. Supplemental Digital Content SDC 1. Supplementary notes to Methods Settings Groote Schuur Hospital is a 975-bed urban academic hospital situated in Cape Town, in the Western Cape province, which provides secondary and tertiary level care, serves as a referral centre for approximately half of the province’s population (2011 population: 5.8 million)1 and is associated with the University of Cape Town. At this hospital we surveyed the general medical wards during May and June 2013. We did not survey the sub-speciality wards (dermatology, neurology, cardiology, respiratory medicine and nephrology), the oncology wards, or the high care / intensive care units. Restricting the survey to general medical wards was done partly due to resource limitations but also to allow the patients at this site to be reasonably comparable to those at other sites, which did not have sub-specialist wards. In 2009, the crude inpatient mortality in the medical wards of Groote Schuur Hospital was shown to be 573/3465 patients (17%)2 and the 12-month post-discharge mortality to be 145/415 (35%).3 Edendale Hospital is a 900-bed peri-urban regional teaching hospital situated near Pietermaritzburg, in the KwaZulu-Natal province (2011 population: 10.3 million).1 It provides care to the peri-urban community and serves as a referral centre for several district hospitals in the surrounding rural area. It is located at the epicentre of the HIV, tuberculosis and multidrug resistant tuberculosis epidemics in South Africa: a post-mortem study in 2008-2009 found that 94% of decedents in the medical wards of Edendale Hospital were HIV-seropositive, 50% had culture-positive tuberculosis at the time of death and 17% of these cultures were resistant to isoniazid and rifampicin.4 At Edendale Hospital, we surveyed the medical wards over 30 days during July and August of 2013.
    [Show full text]
  • Treatment of Drug-Resistant Tuberculosis an Official ATS/CDC/ERS/IDSA Clinical Practice Guideline Payam Nahid, Sundari R
    AMERICAN THORACIC SOCIETY DOCUMENTS Treatment of Drug-Resistant Tuberculosis An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline Payam Nahid, Sundari R. Mase, Giovanni Battista Migliori, Giovanni Sotgiu, Graham H. Bothamley, Jan L. Brozek, Adithya Cattamanchi, J. Peter Cegielski, Lisa Chen, Charles L. Daley, Tracy L. Dalton, Raquel Duarte, Federica Fregonese, C. Robert Horsburgh, Jr., Faiz Ahmad Khan, Fayez Kheir, Zhiyi Lan, Alfred Lardizabal, Michael Lauzardo, Joan M. Mangan, Suzanne M. Marks, Lindsay McKenna, Dick Menzies, Carole D. Mitnick, Diana M. Nilsen, Farah Parvez, Charles A. Peloquin, Ann Raftery, H. Simon Schaaf, Neha S. Shah, Jeffrey R. Starke, John W. Wilson, Jonathan M. Wortham, Terence Chorba, and Barbara Seaworth; on behalf of the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America THIS OFFICIAL CLINICAL PRACTICE GUIDELINE WAS APPROVED BY THE AMERICAN THORACIC SOCIETY, THE EUROPEAN RESPIRATORY SOCIETY, AND THE INFECTIOUS DISEASES SOCIETY OF AMERICA SEPTEMBER 2019, AND WAS CLEARED BY THE U.S. CENTERS FOR DISEASE CONTROL AND PREVENTION SEPTEMBER 2019 Background: The American Thoracic Society, U.S. Centers for was judged to be very low, because the data came Disease Control and Prevention, European Respiratory Society, and from observational studies with significant loss to follow-up Infectious Diseases Society of America jointly sponsored this new and imbalance in background regimens between comparator practice guideline on the treatment of drug-resistant tuberculosis groups. Good practices in the management of MDR-TB are (DR-TB). The document includes recommendations on the described. On the basis of the evidence review, a clinical strategy treatment of multidrug-resistant TB (MDR-TB) as well as tool for building a treatment regimen for MDR-TB is also isoniazid-resistant but rifampin-susceptible TB.
    [Show full text]
  • Of TB Drug Development: What's on the Horizon (For Patients with Or Without
    The ‘third wave’ of TB drug development: What’s on the horizon (for patients with or without HIV) Kelly Dooley, MD, PhD 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, Other Antivirals Noordwijk, The Netherlands 15 May 2019 D I V I S I O N O F CLINICAL PHARMACOLOGY 1 Objectives • To give you an idea of the drug development pathway for TB drugs, the history, and the pipeline • To convince you to come work in the TB field, if you are not already The Problem State-of-the-state: Global burden of TB disease: 2017 In 2014, TB surpassed HIV as the #1 infectious disease killer worldwide In 2017, 10.0M cases TB is estimated to have killed 1 in 7 of humans who have ever lived WHO Global Tuberculosis Report 2018: http://www.who.int/tb/publications/global_report/en/ Latent TB infection (LTBI) About 1 in 4 persons Chaisson and Golub, Lancet Global Health, 2017 MDR- and XDR-TB: Global Health Emergencies Multidrug-resistant TB: Mycobacterium tuberculosis resistant to isoniazid Extensively drug-resistant TB: and rifampin: 558,000 incident cases in 2017 M. tuberculosis resistant to isoniazid, rifampin, fluoroquinolones, and injectable agents Reported in 123 WHO member state countries 6 HIV and Tuberculosis Epidemiology Global Burden of Tuberculosis, 2017 Total Population HIV-Infected Persons Incidence 10.0 million 900,000 (9%) Deaths 1.3 million 300,000 (23%) WHO Report 2018 Global Tuberculosis Control7 TB Treatment: Global Scientific Agenda Area Goals Drug-sensitive TB Treatment shortening to < 3 months More options for patients
    [Show full text]