Antimicrobial Resistance Antimicrobial Resistance

Antimicrobial resistance Antimicrobial resistance

References 1. Chief Medical Officer annual report: volume 2 https://www.gov.uk/government/publications/chief-medical-officer-annual-report-volume-2 2. Antimicrobial resistance: global report on surveillance 2014 http://www.who.int/drugresistance/documents/surveillancereport/en/

Before the widespread use of antibiotics in the 1940s, it was much more common for women to die from post-childbirth infections, and diseases such as tuberculosis were rife. In addition, farmers often faced losing vast numbers of crops and animals to infectious diseases, leading to serious food shortages, even famine. The discovery and introduction of antibiotics gave us the ability to prevent these tragedies. However, as microorganisms become resistant to antimicrobial treatments, including antibiotics, there is a very real possibility that the drugs we have come to rely upon may become obsolete.

Since 1928, when Sir Alexander Fleming accidentally discovered occurrence1. The World Economic Forum has suggested that smart surfaces and medical dressings, are also being developed. penicillin growing on a petri-dish of bacteria, antibiotics have antimicrobial resistance (AMR) be added to the global risk register, This timeline and series of case studies showcase some of these saved the lives of millions of people and animals. Their discovery is and the World Health Organization has highlighted the serious advances, supported by the Biotechnology and Biological seen as one of the most important scientific achievements of the implications for global public health in its AMR Global Report on Sciences Research Council (BBSRC), Engineering and Physical 20th century. But overuse and misuse of antibiotics has Surveillance2. Antimicrobial resistance is one of the Innovative Sciences Research Council (EPSRC) and Medical Research contributed to the emergence of resistance. Sir Alexander Fleming Medicine Initiative’s priorities and a Joint Programming Initiative Council (MRC). This work lays the groundwork for the himself, on collecting a Nobel Prize for his discovery, predicted the on antimicrobial resistance was set up in 2011 to streamline cross-Council antimicrobial resistance initiative that was launched dawn of this battle, saying, “It is not difficult to make microbes European research efforts in AMR. in July 2014. This will see all seven Councils working together to resistant to penicillin in the laboratory by exposing them to tackle AMR. A joined-up, multi-disciplinary approach is essential concentrations not sufficient to kill them…” The UK Research Councils support research, capability and training and so the initiative will coordinate the work of medical to pursue a range of strategies to tackle this global problem. Years researchers, biologists, engineers, vets, economists, social England’s Chief Medical Officer Professor Dame Sally Davies of research mean that we are now in a better position than ever to scientists, mathematicians and designers. It is only through warned in 2013 of the “catastrophic effect” of antimicrobial understand microbes such as bacteria, viruses and fungi, how tackling the problem at every level and in every environment that resistance and urged immediate action from global leaders before they interact with their hosts, and to identify possible routes for we will be able to take the next steps towards a solution. deaths from routine surgery once again become a common alternative diagnostics and treatments. New technologies which could help prevent the spread of bacteria and infections, including

2007: 2010: 2011: University of Newcastle spin-out company The EU uses the results of research by Scientists at the MRC Research changes from its normal form to a e-Therapeutics Ltd identifies three BBSRC David Phillips Fellow Dr Mark Complex at Harwell determine the slow-growing antibiotic-resistant form drugs that are effective against Webber in two reports on the use of structure of NDM-1 using the STFC’s as part of its natural lifestyle to ensure antibiotic-resistant superbugs, common biocides3. During his fellowship, Diamond Light Source crystallography its survival10. including MRSA, using Grid computing Dr Webber characterised the genetic facility7. Understanding the structure and e-science techniques developed changes that grant Salmonella resistance will help researchers develop drugs that during research funded by EPSRC and the to the biocide triclosan and others4. There could inactivate the enzyme or that Department of Trade and Industry1. The were around 9,000 cases of Salmonella are not susceptible to it. Bacteria transmit resistance genes to company searched through tens of food poisoning in the UK in 2010, other bacterial strains by way of millions of compounds for any that although three quarters of cases may plasmids — small loops of DNA. Carrying showed action against superbugs in a go unreported5. these plasmids is commonly thought to fraction of the time it would take using Professor Hagan Bayley at the University ‘community-acquired’ MRSA strains, which reduce a bacterium’s fitness, so removal conventional drug discovery methods. of Oxford discovers that the antibiotic- can both resist antibiotics by making of antibiotic pressure should reduce the resistance of Escherichia coli is not due to changes to the bacterial cell wall and number of resistant bacteria. However, in the reduced size of OmpC — the channel maintain high levels of toxin production. a BBSRC and MRC-funded study, Professor 2008: in the bacteria’s membrane that allows Laura Piddock and Dr Mark Webber at the The first case of a bacterial infection with the entry of antibiotics — as is the cause University of Birmingham discover that resistance caused by NDM-1, a powerful of much resistance, but a change in its the plasmid pCT persists in the absence of enzyme that gives bacteria resistance electrostatic field8. Dr Andrew Edward at the MRC Centre antibiotics because it has evolved to have to most antibiotics, is discovered2. for Molecular Bacteriology and Infection little impact on the host11. They conclude MRC-funded researcher Professor Tim (CMBI), Imperial College London, that resistance genes will persist even with Walsh was part of the group that 2012: demonstrates that Staphylococcus aureus careful rationing of antibiotics. identified the enzyme, which is commonly BBSRC-funded researchers find a protein The gene which grants one strain of MRSA produced by Escherichia coli and Klebsiella on the surface of Streptococcus uberis found in hospitals resistance to a range pneumonia, but can also spread bacteria, responsible for bovine mastitis, of antibiotics also reduces the bacteria’s between different strains of bacteria. which plays a central role in enabling the ability to secrete the toxins that bacteria to cause disease6. The findings cause illness, according to a BBSRC and suggest it may be possible to develop MRC-funded study led by Dr Ruth Massey a vaccine against the disease, reducing at the University of Bath9. The results also farmers’ reliance on antibiotics. highlight the problem of

In an MRC-funded study, Professor Gad and also increases its resistance to many conditions, such as those found in the stop growing and to use minimal Professor Laura Piddock at the University Frankel at Imperial College London uses a other antibiotics and the biocide triclosan, lungs of people with severe respiratory resources. The CMBI researchers of Birmingham sequences the plasmid mouse infected with bacteria genetically according to research by Professor Laura illnesses, including cystic fibrosis17. show that a protein called NtrC plays a pCT, which confers antibiotic resistance modified to produce light to show how an Piddock and Dr Mark Webber at the P. aeruginosa infection is one of the most central role in the process by controlling to bacteria carrying it. She concludes that infection moves around the body in real University of Birmingham15 and supported common causes of death in cystic the level of ppGpp. the plasmid’s success lies in its stability time12 & 13. Regular CT scans of the mouse by BBSRC and the MRC. fibrosis patients. in a range of hosts, the lack of a fitness could show how different vaccines and cost to the host bacteria — meaning that antibiotics change the way bacteria take carrying the plasmid has no detrimental over parts of the body. Researchers at the London Centre for effect — and efficient transfer between MRC-funded Professor Guy Frankel Nanotechnology, University College bacterial hosts20. at Imperial College shows how London, show how drug-binding 2013: enteropathogenic Escherichia coli (EPEC), mechanically weakens bacterial cells A research team from the Universities of a pathogenic strain of E.coli which is a and leads to their death, whilst unravelling Nottingham, Birmingham and Newcastle, common cause of infant diarrhoea in the how the antibiotic vancomycin works. funded by EPSRC and BBSRC, discover developing world, interferes with the host Vancomycin is one of the few effective that artificial materials based on simple cell’s normal antimicrobial response16. treatments for MRSA. The study was synthetic polymers can disrupt the way in EPEC injects a toxin into host cells during funded by EPSRC, BBSRC and the which bacteria communicate with each infection. This blocks the cell’s ability to Royal Society. other. The findings14 open up the send messages to the immune cells, possibility to influence microbial preventing a response and subsequent 2014: behaviour by controlling their ability to death of the infected cells, allowing the BBSRC-funded researchers at the MRC form productive communities, which bacteria to survive and spread. Centre for Molecular and Biomolecular Researchers at the MRC Centre for could be exploited to prevent the release Informatics (CMBI), identify the pathway Molecular Bacteriology and Infection of toxins during the spread of infection. behind the ‘stringent response’, the (CMBI) study ‘persister’ cells in Salmonella, mechanism E.coli use to survive when visualising them for the first time using a BBSRC-funded researchers at the under stress, such as when deprived of fluorescent protein produced by the University of Cambridge find the gene nutrients or in the presence of bacteria. Persister cells are a non- A common mutation in Salmonella grants responsible for activating the infection antibiotics18. When under stress, bacteria replicating form of the bacteria and the bacteria resistance to an important mechanism in Pseudomonas aeruginosa produce guanosine tetraphosphate ‘lie low’ to evade antibiotic action19. class of antibiotics, the fluoroquinolones, when the bacteria encounter low oxygen (ppGpp), which instructs the bacteria to See ‘Antibiotic-evading bacteria’.

1985: 2005: 2009: Researchers at the John Innes Centre (JIC), by BBSRC at the University of Oxford. In Dr Curtis Dobson founds spin-out The company has since identified two Professor Jeremy Lakey co-founds which receives strategic funding from 2009 Prolysis is acquired by Australian company Ai2 to develop an anti-infective promising protein targets for use in spin-out company OJ-Bio, based on BBSRC, led by Dr David Hopwood, are the drug development firm Biota. coating for contact lenses. The anti- vaccines. BBSRC-funded research at Newcastle first to produce a ‘hybrid’ antibiotic using infective arose from Dr Dobson’s University, to develop miniature wireless genetic engineering, alongside colleagues BBSRC-funded research at the University sensors that can be used to test for a from Japan and the USA21. The researchers 2002: of Manchester into a protein that could diverse range of infectious diseases in transferred genes associated with The Streptomyces genome, sequenced help protect against the viral infections Demuris, Professor Jeff Errington’s second humans31. The devices are currently being antibiotic production between strains by BBSRC- and Wellcome Trust-funded associated with Alzheimer’s disease27. spin-out company, is founded, based on evaluated by commercial partners in the of Streptomyces bacteria, enabling the researchers, is published in the journal BBSRC-funded research. The company is healthcare industry to test for infectious bacteria to produce an entirely new Nature23. Researchers subsequently using a unique collection of actinomycete diseases including flu, HIV and gum antimicrobial compound. discover a large number of previously- bacteria, together with Professor disease. Further funding has been unknown gene clusters in the Errington’s understanding of bacterial cell provided by the EPSRC and Technology Streptomyces genome that produce biology, to look for potentially valuable Strategy Board (now Innovate UK) to 1998: ‘specialised metabolites’, potentially new natural products, including develop the technology. Professor Jeff Errington founds spin-out including previously-unknown antibiotics29. company Prolysis to develop and antimicrobials. commercialise screening techniques to find novel antibiotics to tackle drug- 2008: resistant bacterial infections22. The 2003: Procarta Biosystems is co-founded by company is based on fundamental JIC spin-out company Novacta Professor Mervyn Bibb and Dr Michael bacterial cell biology research supported Biosystems24 is founded to discover and 2007: McArthur at JIC to develop and develop potential treatments for Professor Simon Foster and Dr Jorge commercialise a new class of antibiotics, infectious diseases, particularly those Garcia-Lara at the University of Sheffield DNA-based transcription factor decoys caused by antimicrobial-resistant bacteria. create spin-out company Absynth (TFDs), to combat infections caused by Their lead product, based on a long Biologics to develop vaccines against S. drug-resistant bacteria30. TFDs work by history of Streptomyces research at JIC25, aureus infection, including MRSA28. blocking the action of ‘transcription is designed to treat infections caused by Absynth arose from Professor Foster’s factor’ proteins that control the the bacterium Clostridium difficile; BBSRC and MRC-funded research into S. expression of large numbers of genes which was involved in 2,704 deaths in the aureus, and in particular the genes within the bacterial cells. UK in 201026. See ‘New antibiotics from essential for its survival. bacterial bioscience’. © Medical Research Council 2014 Antimicrobial resistance

MRC and BBSRC-funded researcher Researchers at the MRC Laboratories in well as reduce the overuse of antibiotics. Predatory bacteria with the potential bacteria could combine two antibiotic Professor Adam Cunningham at the The Gambia, in collaboration with The research team was funded by the to be used as ‘living antibiotics’ are safe molecules to produce a much more Universityof Birmingham begins scientists in the US, find that infection EPSRC and Ministry of Defence. See when ingested by chickens, according to effective antibiotic, which works development of a vaccine against with H.pylori – the bacterium ‘Wound dressing provides glowing BBSRC-funded researchers from the against MRSA. Salmonella32. The vaccine development responsible for gastritis and gastric ulcers evidence of infection’. University of Nottingham38. When given has been licensed to Novartis Vaccines – may protect the host against other to live, Salmonella-infected chickens, Institute for Global Health. pathogens, such as tuberculosis35. Bdellovibrio bacteria reduced the number of Salmonella cells by 90 per cent while Scientists at the Institute of Food Funded by the MRC, Dr Andrew Gorringe leaving the birds unharmed. Research (IFR), which receives strategic 2010: at the Health Protection Agency develops funding from BBSRC, adapt the structure A team of researchers at the MRC Centre a vaccine against bacterial meningitis. of the protein endolysin, derived from for Molecular Bacteriology and Infection The vaccine is currently being developed a bacteriophage virus, so that it is more (CMBI), with funding from BBSRC, reveal with funding from the Biomedical Catalyst Researchers are using synthetic biology effective against C. difficile, a common the structure of a protein called Gp2, by ImmBio, a vaccine development approaches to alter antibiotic production cause of hospital-acquired infections, produced by the ‘bacteriophage’ virus T7, company based at the Babraham in marine bacteria to produce new hybrid while remaining ineffective against which disables E.coli cells33. Bacteriophage Research Campus36. antibiotics39. The BBSRC- and EPSRC- beneficial gut bacteria40. viruses infect and kill many bacterial funded researchers, from the University species, including those that cause of Birmingham and working with others in human and animal diseases. See the UK and Japan, found that the marine 2012: ‘Bacteria-eating viruses’. BBSRC-funded researchers begin to BBSRC-funded researchers at the MRC develop a new type of vaccine to protect Centre for Molecular Bacteriology and 2011: chickens against coccidiosis37, based on a Infection (CMBI) demonstrate how Gp2 A Sheffield University research team single protein that plays a vital role in the interacts with the bacteria’s RNA Ai2, the spin-out company established by produce a gel containing molecules that early stages of infection. The coccidiosis polymerase — an enzyme that enables Dr Dobson at the University of bind to bacteria and activate a parasite, which is widely resistant to the instructions in the bacteria’s genes to Manchester, announces a multimillion fluorescent dye. The gel will be used in antimicrobials, is the most important be read and turned into proteins — pound licencing deal with UK-based wound dressings to indicate when an parasite of poultry globally. to stop it from functioning41. The contact lens and aftercare manufacturer infection has developed and will help scientists now plan to identify small Sauflon to use the anti-infective coating clinicians to make rapid, informed in their products34. decisions about wound management as

2013: molecules that mimic the structure and MRC-funded researchers at the Wellcome An EPSRC Interdisciplinary Research Absynth Biologics receives more than £2M function of Gp2 and use these as the Trust Sanger Institute demonstrate that Centre46 is established at University through the Technology Strategy basis for new drugs to combat treatment of C. difficile-infected mice College London to create a new Board- and MRC-funded Biomedical bacterial infections. with faeces from healthy mice rapidly generation of early-warning sensing Catalyst to take forward to a pre-clinical restores a diverse, healthy microbiota systems to diagnose, track and prevent stage its vaccine against MRSA. and subsequently cures the disease and the spread of infections, including removes its contagiousness44. influenza, antimicrobial resistance and Novacta Biosystem’s lead product, HIV, using mobile communication, NVB302, which is being developed to treat nanotechnology, genomics and big data A team led by MRC-funded researcher C. difficile infections, completes phase MRC-funded researcher Professor Robert analysis to actively manage outbreaks and Dr Martha Clokie at the University of I clinical trials, showing it is safe when Akid at the University of Manchester prevent infectious diseases. Leicester isolates 40 different administered to healthy people42. patents an antimicrobial coating for bacteriophages — viruses that ‘eat’ cementless prostheses, such as hip and bacteria — against hospital superbug C. knee replacements, to prevent infection45. difficile. US pharmaceutical company The controlled release ensures the The world’s largest antibody search AmpliPhi Biosciences Corporation are JIC and University of Oxford researchers antimicrobial is released only at the engine, CiteAb47, is founded by funding the further development of these begin a BBSRC-funded project to appropriate time (during and EPSRC-funded Dr Andrew Chalmers at the phages. See ‘Bacteria-eating viruses’. investigate whether they can use after surgery). University of Bath. The service, which synthetic biology to remove the toxic allows researchers to find antibodies for side effects of tunicamycin; an antibiotic use in their research, is the largest 2014: produced by the soil bacterium antibody search engine in a $2Bn antibody Imperial College London scientists, with Streptomyces43. See ‘New antibiotics from industry, and ranked number one by support from BBSRC, identify how a bacterial bioscience’. Google. Ranking antibodies by academic protein, called P7, produced by a certain citations means CiteAb provides an bacteriophage virus disables an essential independent, verifiable guide as to bacterial enzyme called RNA whether an antibody is likely to work in polymerase48. The viral protein uses a the laboratory, saving both time previously-unknown method to disable and money. the RNA polymerase, which is involved in bacterial gene expression, by preventing it from identifying target genes.

2007: A peptide molecule found in American fungus that provides them In an MRC-funded study, Professor researchers from Bristol’s Frenchay live in a chicken’s gut56. Chickens and other Bullfrogs is being developed to treat with food, protecting their nest against Timothy Walsh sequences K. pneumonia hospital and Bedfordshire based farm animals can act as a reservoir of wounds infected with MRSA49. Researchers infection and controlling competing containing NDM-1 from three different AmpliPhi Biosciences, uses dye-filled human pathogens and of microbes that led by Dr Peter Coote at the University of strains of fungi51. countries and shows that there is great nanocapsules that burst open in the carry antimicrobial resistance genes. The St Andrews find that the bullfrog peptide diversity between the strains. He finds presence of disease-causing bacteria. researchers, with support from BBSRC, ranalexin can inhibit MRSA growth when that one of the most common strains, Using a UV light, clinicians can quickly used high-throughput sequencing to combined with another antimicrobial, 2011: ST14, is associated with the most invasive check whether there is any infection by rapidly sequence the DNA of microbes in lysostaphin. The researchers patent the Materials scientists at the University of form of the disease53. seeing if the dressing lights up. the chicken gut to identify which bacterial discovery and aim to develop effective Birmingham, funded by EPSRC, devise a species were present. treatments for MRSA-infected wounds. way of making stainless steel surfaces resistant to bacteria by introducing silver or copper into the surface rather than Researchers at the University of Sheffield applying it as a coating. The technique discover that combinations of bacteria, Some strains of MRSA that cause disease could prevent the spread of superbug commonly found in water pipes, can form in humans originate in livestock, infections on stainless steel surfaces in a ‘biofilm’ that enables other, potentially according to research led by Professor hospitals as well as medical equipment harmful, bacteria to thrive55. The Ross Fitzgerald at the Roslin Institute, such as instruments and implants, the EPSRC-funded study isolated four types of which receives strategic funding from food industry, and domestic kitchens. bacteria and found that when any of them BBSRC57. The findings suggest that grew alongside bacteria called livestock can act as a potential reservoir Methylobacterium, they formed a biofilm of new human epidemic strains of the 2010: 2012: within 72 hours. The findings mean it bacteria. See ‘Making the leap’. Bacteria carried on the surface of Researchers at the University of should be possible to control the creation leafcutter ants produce a range of Nottingham, funded by BBSRC and the of biofilms in water supplies by targeting antimicrobial compounds, according to a Wellcome Trust, discover a new class of 2013: particular bacteria. study by BBSRC and MRC-funded material that resists colonisation by EPSRC-funded researchers develop a researchers from the University of East bacteria52. The materials, known as method for quickly detecting infections in Anglia, JIC, and The Genome Analysis synthetic acrylate polymers, have been children with serious burns54. Children are Centre (TGAC), which receives strategic licensed to UK company Camstent Ltd, at higher risk than adults from the effects Researchers at the University of Warwick funding from BBSRC50. The antimicrobials which is now working with the academics of subsequent infection. The dressing, adopt a DNA-based approach to under help the ants cultivate a to develop coated urinary catheters. developed at the University of Bath with stand the community of microbes that

MRC-funded Professor Sharon Peacock The Chief Medical Officer publishes the at the University of Cambridge uses second volume of her annual report, whole-genome sequencing to analyse focusing on infection and antimicrobial an outbreak of MRSA58. Whole genome resistance. Professor Peacock writes a sequencing of bacterial samples could section on the use of whole genome lead to fewer antibiotics being used as sequencing to track the transmission of a more specific diagnosis would allow infections to improve surveillance the targeted use of specific antibiotics and control59. to treat it. This sequencing also means that researchers can track the spread of infection, helping with infection control and prevention. See ‘Whole-genome An MRC-funded team at the University of sequencing’. Oxford, led by Dr David Eyre and Dr Sarah Walker, use whole genome sequencing to show that many cases of C. difficile infection are caused by bacteria transmitted from people who show no sign of infection, or from environmental sources such as water, animals, or food, rather than from symptomatic patients60. See ‘Whole-genome sequencing’.

2005: With up to 50 per cent of antibiotic antibiotics should be used if a patient the British Pig Executive to develop ensure antimicrobials are prescribed surfaces far from infected patients’ beds68. prescribing inappropriate61, Professor Peter requires a second course of antibiotics monitoring systems to help farmers appropriately. The app is used over 4,800 Coughing, sneezing or shaking bedclothes Davey at the University of Dundee looks within 12 weeks of the first. identify animals at risk of PWMS. times in the first month. 85 per cent can send superbugs into the air, allowing at interventions to improve prescribing, of users responding to a post- them to contaminate recently cleaned such as education, restriction of drugs, implementation survey considered surfaces. This may explain why, guideline implementation and expert that the IAPP added to their knowledge despite strict cleaning regimes and approval in an MRC-funded study62. It was previously thought that using less base regarding antimicrobial prescribing hygiene controls, some hospitals still active antibiotics was the best first and 96 per cent found that it influenced struggle to prevent bacteria moving defence in order to reserve more active their prescribing practice. from patient to patient. 2007: antibiotics for more resilient bacteria. In In an MRC-funded study, Professor David an MRC-funded study, Professor Sebastian Mant at the University of Oxford shows Amyes at the University of Edinburgh 2013: that antibiotic-resistant bacteria are concludes that using less active antibiotics Professor Ian Chopra, director of the The Joint Programming Initiative on present in children prescribed the first — which are generally more likely to Antimicrobial Research Centre at the Antimicrobial Resistance publishes its common antibiotic amoxicillin, which cause resistance to develop — results University of Leeds advocates that new Strategic Research Agenda69. MRC-funded although transitory in the children is in resistance to the whole class of business models for antibiotic Professors Tim Walsh and Paul Williams sufficient to sustain a high-level of antibiotics, rendering even the more development are required. He suggests were involved in its development. antibiotic resistance in the population63. active types unusable64. new methods of screening for The findings provide clinicians with compounds, delinking product sales guidance on which from the companies’ return on investment 2014: 2011: and financing incentives for An international team of researchers, Pigs on farms with access to the outdoors drug development67. including MRC-funded researcher and a clean, enriched environment are The Imperial Antibiotic Prescribing Policy Dr Tim Felton, recommend individualised less likely to suffer Post Weaning (IAPP) smartphone app is developed by antibiotic dosing for critically-ill patients70. Multi-systemic Wasting Syndrome Imperial College Healthcare NHS Trust’s 2012: These patients often exhibit different (PWMS), which is associated with a certain antibiotic review group and the UKCRC EPSRC-funded researchers at the responses to antibiotic treatment; dosing virus, than those on other farms, Centre for Infection Prevention and University of Leeds discover that that does not take this into consideration according to BBSRC-funded researchers Management66. The app helps healthcare superbugs, such as MRSA and C. difficile, can lead to sub-optimal treatment and from the Royal Veterinary College65. professionals choose the most not only spread through contact, but they increase antibiotic resistance. The researchers are now working with appropriate course of treatment to also float on air currents and contaminate

EPSRC-funded researchers at Newcastle University and the Indian Institute of Technology in Delhi reveal that the spread of antibiotic-resistance at sacred sites along the Ganges is linked to annual human pilgrimages. When thousands of visitors travelled to the sacred sites, levels of resistance genes in bacterial populations were about 60 times greater than other times of the year. The study is helping to understand how resistance gene blaNDM-1 spreads through specific human activity71.

The World Health Organization publishes its report Antimicrobial resistance: global report on surveillance 201472. Professor Tim Walsh was part of the review group.

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References 24. Novacta Biosystems: http://www.novactabio.com/ 25. History of Streptomyces research at JIC: http://www.bbsrc.ac.uk/publications/impact/streptomyces-bacteria.aspx. 26. C. difficile statistics: http://www.ons.gov.uk/ons/rel/subnational-health2/deaths-involving-clostridium-difficile/2006-to-2010/statistical-bulletin.html. 27. Dobson, CB, Sales, SB, Hoggard, P, Wozniak, MA, & Crutcher, KA (2006) The Receptor-Binding Region of Human Apolipoprotein E Has Direct Anti-Infective Activity. The Journal of Infectious Diseases. 193 (3), pp. 442-450. DOI: oi: 10.1086/499280. 28. Absynth Bioloics impact case study: http://www.bbsrc.ac.uk/publications/impact/absynth.aspx 29. See full details at: http://www.bbsrc.ac.uk/publications/impact/prolysis-demuris.aspx 30. See: https://www.jic.ac.uk/staff/michael-mcarthur/procarta.htm 31. See full details at: http://www.bbsrc.ac.uk/publications/impact/wireless-disease-detector.aspx 32.http://www.google.com/patents/WO2010029293A1?cl=en. 33.Camara B, Liu M, Reynolds J, et al (2010). T7 phage protein Gp2 inhibits the Escherichia coli RNA polymerase by antagonizing stable DNA strand separation near the transcription start site, Proceedings of the National Academy of Sciences of the United States of America. 107, p 2247-2252. 34. See: http://www.a-i-2.com/news/?id=18 35. Perry S et al (2010). Infection with Helicobacter pylori Is Associated with Protection against Tuberculosis PLoS ONE 2010; 5(1):e8804. 36. http://webarchive.nationalarchives.gov.uk/20130221185318/www.innovateuk.org/_assets/pdf/casestudies/NewVaccine_Immbio_0910_v4.pdf . 37. Lai L, Bumstead J, Liu Y, Garnett J, Campanero-Rhodes MA, Blake DP, Palma AS, Chai W, Ferguson DJP, Simpson P, Feizi T, Tomley FM, Matthews S (2011). The role of sialyl glycan recognition in host tissue tropism of the avian parasite Eimeria tenella. PLoS Pathogens. 2011.7(10) e1002296. 38. Atterbury RJ, Hobley, L, Till, R, Lambert, C, Capeness, MJ, Lerner, TR, Fenton, AK, Barrow, P, Sockett, RE. (2011). Studying the effects of orally administered Bdellovibrio on the wellbeing and Salmonella colonization of young chicks. Applied and Environmental Microbiology. DOI: 10.1128/AEM.00426-11. 39. Murphy AC, Fukuda D, Song Z, Hothersall J, Cox RJ, Willis CL, Thomas CM, Simpson TJ. (2011). Engineered thiomarinol antibiotics active against MRSA are generated by mutagenesis and mutasynthesis of Pseudoalteromonas SANK73390. Angew Chem Int Ed Engl. 50(14):3271-4. doi: 10.1002/anie.201007029. 40. Mayer MJ, Garefalaki V, Spoerl R, Narbad A, Meijers R. (2011). Structure-based modification of a Clostridium difficile-targeting endolysin affects activity and host range. J Bacteriol. 193(19):5477-86. doi: 10.1128/JB.00439-11. 41. James, E et al (2012). “Structural and Mechanistic Basis for the Inhibition of Escherichia coli RNA Polymerase by T7 Gp2.” Molecular Cell, 2012.DOI: http://dx.doi.org/10.1016/j.molcel.2012.06.013. 42. Novacta news article: http://www.novactabio.com/news.php. 43. See: http://www.bbsrc.ac.uk/pa/grants/AwardDetails.aspx?FundingReference=BB%2fJ009725%2f1. 44. Lawley TD et al (2012). Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice PLOS Pathogens 2012;8(10):e1002995. doi: 10.1371/journal.ppat.1002995. 45. http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2328627B1&KC=B1&FT=D . 46. http://www.ucl.ac.uk/infection-sense 47. http://www.citeab.com/ 48. Liu, B et al. (2014) A bacteriophage transcription regulator inhibits bacterial transcription initiation by sigma-factor Displacement. Nucleic Acids Research. 1-12. doi:10.1093/nar/gku080. 49. Graham S, Coote PJ (2007). Potent, synergistic inhibition of Staphylococcus aureus upon exposure to a combination of the endopeptidase lysostaphin and the cationic peptide ranalexin. J Antimicrob Chemother. 59(4):759-62. 50. Barke J, Seipke RF, Grüschow S, Heavens D, Drou N, Bibb MJ, Goss RJ, Yu DW, Hutchings MI (2010). A mixed community of actinomycetes produce multiple antibiotics for the fungus farming ant Acromyrmex octospinosus. BMC Biol. 8:109. doi: 10.1186/1741-7007-8-109. 51. Barke J et al (2010). A mixed community of actinomycetes produce multiple antibiotics for the fungus farming ant Acromyrmex octospinosus. BMC Biol. 2010; 8: 109. Published online Aug 26, 2010. doi: 10.1186/1741-7007-8-109.

References 52. Hook, A, C, C-Y, Yang, J, Luckett, J, Cockayne, A, Atkinson, S, Mei, Y, Bayston, R, Irvine, D, Langer, R, Anderson, D, Williams, P, Davies, M, and Alexander, MR. Combinatorial discovery of polymers resistant to bacterial attachment. Nature Biotechnology (2012), 30, 868. (IF=32.4) PMID: 22885723. 53. Giske CG et al (2012). Diverse Sequence Types of Klebsiella pneumoniae Contribute to the Dissemination of blaNDM-1 in India, Sweden, and the United Kingdom. Antimicrob Agents Chemother. May 2012; 56(5): 2735–2738. 54. Jenkins, T (2012). Anti-microbial burn dressing fights bacterial infection: University of Bath research. University of Bath. 55. Biggs CA, Ramalingam B, Sekar R & Boxall JB (2013). Aggregation and biofilm formation of bacteria isolated from domestic drinking water. 56. Video transcript describing project: http://www.bbsrc.ac.uk/news/videos/1306-v-what-lives-inside-a-chicken-pt2-transcript.aspx. 57. Spoor LE, McAdam PR, Weinert LA, Rambaut A, Hasman H, Aarestrup FM, Kearns AM, Larsen AR, Skov RL, Fitzgerald JR. (2013) Livestock origin for a human pandemic clone of community-associated methicillin-resistant Staphylococcus aureus. MBio. 4(4). pii: e00356-13. 58. Harris SR et al (2013). Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study. The Lancet Infectious Diseases Volume 13, Issue 2, February 2013, Pages 130–136. 59. Chief Medical Officer annual report: volume 2 https://www.gov.uk/government/publications/chief-medical-officer-annual-report-volume-2. 60. Eyre DW et al (2013). Diverse Sources of C. difficile Infection Identified on Whole-Genome Sequencing. N Engl J Med 2013; 369:1195-1205 September 26, 2013 DOI: 10.1056/NEJMoa1216064. 61. House of Lords Select Committee on Science and Technology. Resistance to antibiotics and other antimicrobial agents. Session 1997-98. 7th Report. London: The Stationary Office, 1998:1-108. 62. Davey P et al (2005). Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003543. 63. Chung A et al (2007). Effect of antibiotic prescribing on antibiotic resistance in individual children in primary care: prospective cohort study. BMJ 2007;335:429. 64. Amyes SGB et al (2007). Best in class: a good principle for antibiotic usage to limit resistance development? J. Antimicrob. Chemother. (2007) 59 (5): 825-826. doi: 10.1093/jac/dkm059 First published online: March 29, 2007. 65. Alarcon, P, Velasova, M, Mastin, A, Nevel, A, Stark, KDC, Wieland, B. Farm level risk factors associated with severity of post-weaning multi-systemic wasting syndrome. Preventive Veterinary Medicine 101 (2011), pp.182-191. 66. Smartphone application for antibiotic prescribing. Showcase Hospitals Local Technology Review Report number 6. https://www.gov.uk/government/publications/smartphone-application-for-antibiotic-prescribing. 67. So AD et al (2011). Towards new business models for R&D for novel antibiotics. Drug Resist Updat. 2011 Apr;14(2):88-94. doi: 10.1016/j.drup.2011.01.006. Epub 2011 Mar 25. 68. King, MF, Noakes, CJ, Sleigh, PA, Camargo-Valero, MA (2012). ‘Bioaerosol Deposition in Single and Two-Bed Hospital Rooms: A Numerical and Experimental Study’ Building and Environment. 69. http://www.jpiamr.eu/slider/strategic-research-agenda/ 70. Roberts JA et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. The Lancet Infectious Diseases. Volume 14, Issue 6, June 2014, Pages 498–509. DOI: 10.1016/S1473-3099(14)70036-2. 71. Ahammad ZS, Sreekrishnan TR, Hands CL, Knapp CW, Graham DW (2014). Increased Waterborne blaNDM-1 Resistance Gene Abundances Associated with Seasonal Human Pilgrimages to the Upper Ganges River. Environmental Science and Technology. 2014, 48 (5), pp 3014–3020. DOI: 10.1021/es405348h. 72. http://www.who.int/drugresistance/documents/surveillancereport/en/

References

Front cover Petri dishes with cultures of bacteria grown on agar jelly. Credit: M J Richardson. CC BY 3.0

Understanding resistant bacteria in context of the host Image 1: Salmonella invading cultured human cells. Credit: NIAID. CC BY 2.0 Image 2: NDM-1 was first identified in Klebsiella pneumonia bacteria. Public domain. Image 3: Pills. Credit: Thinkstock Image 4: A scanning electron micrograph of Pseudomonas aeruginosa bacteria. Credit: CDC/Janice Haney Carr. Public domain. Image 5: A scanning electron micrograph of MRSA and a dead human white blood cell. Credit: NIAID. CC BY 2.0

Accelerating therapeutic and diagnostics development Image 1: Slide culture of Streptomyces sp. Credit: US Centers for Disease Control and Prevention. Public Domain. Image 2: Contact lenses. Credit: Thinkstock Image 3: OJ-Bio’s prototype medical diagnostic device. Credit: OJ-Bio. Image 4: Vaccine. Credit: iStock Image 5: A chicken. Credit: Liz West CC BY 2.0 Image 6: The connectedness of today’s society. Credit: Thinkstock.

Understanding the real world interactions Image 1: American Bullfrog Rana catesbeiana. Credit: Fir0002. CC BY-SA 2.5 Image 2: Surgical instruments. Credit: Thinkstock Image 3: Cows on Eifee Hill. Credit: John Comloquoy CC BY-SA 2.0 Image 4: Automated DNA sequencing output of human chromosome 1. Credit: Wellcome Images/The Sanger Institute.

Behaviour within and beyond the healthcare setting Image 1: Pigs. Credit: Hadyn Blackey. CC BY-SA 2.0 Image 2: The Imperial Antibiotic Prescribing Policy smartphone app. Credit: Imperial College London.

Image: Salmonella coloured green growing in macrophages. Credit: MRC Centre for Molecular Bacteriology and Infection, Imperial College London.

Researchers at the MRC Centre for Molecular Bacteriology and Infection (CMBI) at Imperial College London are studying dormant ‘persister’ cells produced by Salmonella bacteria. These cells are formed by bacteria when they are exposed to stresses such as antibiotics. By studying persister cells, the researchers hope to understand the link between these dormant cells and antibiotic resistance, as well as develop treatments that target persister cells directly.

Most antibiotics act only on active bacteria. But nearly all bacterial mechanisms behind this evasion are identified to help develop laboratory media. The researchers demonstrated that the bacteria pathogens produce a small sub-population of dormant cells that appropriate strategies to treat these persisters. Despite their formed persisters immediately after being attacked and can evade antibiotics. These cells — called persisters — tolerate discovery by Joseph Biggar more than 70 years ago2, persister consumed by the host’s white blood cells in response to the levels antibiotics and other environmental stresses, such as nutrient cells are still poorly understood. of acidity and lack of nutrients inside the cells. depletion or host cell acidity. Once the stress has been removed, for example, by the completion of a course of antibiotics, the Persisters and resistance These stresses also cause some bacterial cells to start replicating dormant cells are able to revert back to the active, disease-causing Up until now, persister cells have only been studied in test tubes. rather than form persister cells, and this dual response allows form. These cells are thought to be the cause of many persistent However, in 2014, a team led by Professor David Holden at the bacteria to ‘hedge their bets’ to gives them a selective advantage. or recurrent infections. CMBI used a technique they had developed to visualise persisters for the first time at the single-cell level as they are consumed by Professor Holden is now hoping to use these approaches to study This antibiotic ‘tolerance’ is temporary and reversible, unlike white blood cells3. how persister cells might lead to resistance. resistance, which is caused when the bacteria acquire stable “It is widely thought that the multiple courses of antibiotics made genetic traits. However, it is thought that prolonged and Using a fluorescent protein, Professor Holden and colleagues necessary by persistent infections leads to resistance. However, repeated treatment of persistent infections may lead to showed that the bacteria produced persister cells when consumed this has not been tested experimentally. Since the genetic basis of genetic drug resistance1, and so it is important that the by white blood cells at a much greater rate than when grown in persister formation has been worked out in recent years, we

Targeting persisters inefficient to one that kills these persistent bacteria9. can make bacterial mutants with enhanced or reduced persister Pyrazinamide is the only drug that specifically targets persister frequency and use these in conjunction with our techniques cells. In 1970 researchers at the MRC Tuberculosis and Chest “Another possibility is to work out what triggers the persister to determine if and how persisters contribute to emergence of Diseases Unit5 demonstrated for the first time that the inclusion cells to start growing again — give someone with a persistent resistance during infection,” says Professor Holden. of pyrazinamide in an antibiotic regimen for the treatment of infection a drug that induces this — and then attack the bacteria Mycobacterium tuberculosis substantially reduced the relapse as they come out of hiding,” says Professor Holden. Surviving adverse conditions rate6. Certain antibiotics however do have limited action against Part of Professor Michael Barer’s research at the University of the persisters and REMoxTB, a clinical trial involving several MRC Leicester looks at the transmission and persistence of researchers, is currently underway to determine whether the Mycobacterium tuberculosis. In 2008 he, together with colleagues inclusion of the antibiotic moxifloxacin can shorten the duration at the MRC unit, The Gambia, demonstrated that the tuberculosis of treatment7. bacteria in samples of sputum — the mucus and other matter brought up from the lungs by coughing, and which helps transmit Enhancing the host’s immune response is another method of the disease between people — were likely to be in their persistent targeting persister cells8. The bacillus Calmette-Guerin (BCG) state. These samples contained a fat called triglyceride, produced vaccine has limited success as a preventative measure. However, by the bacteria when they form persister cells. This suggests that researchers at the MRC’s National Institute of Medical Research formation of the persisters might help the bacteria survive the (NIMR) showed that the use of the M. tuberculosis Hsp60 DNA adverse conditions that M. tuberculosis encounters when it vaccine, in combination with antibacterial treatment, was is transmitted between people4. successful in treating heavily infected mice. The DNA vaccinations can switch the immune response from one that is relatively

References 1. Zhang Y. Persisters, persistent infections and the Yin–Yang model. Emerging Microbes & Infections (2014) 3, e3; doi:10.1038/emi.2014.3 2. Hobby GL, Meyer K, Chaffee E. Observations on the mechanism of action of penicillin. Proc Soc Exp Biol NY 1942; 50: 281–285. 3. S. Helaine et al. ‘Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating Persisters.’ Science, 10 January 2014. Vol. 343 no. 6167 pp. 204-208 DOI: 10.1126/science.1244705 4. Garter J et al. Cytological and Transcript Analyses Reveal Fat and Lazy Persister-Like Bacilli in Tuberculous Sputum. PLOS Medicine Published: April 01, 2008 DOI: 10.1371/journal.pmed.0050075 5. Closed in 1986. 6. Fox et al. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. The International Journal of Tuberculosis and Lung Disease, Volume 3, Supplement 2, October 1999, pp. S231-S279(49) 7. http://clinicaltrials.gov/ct2/show/NCT00864383 8. Zhang Y et al. Targeting Persisters for Tuberculosis Control Antimicrob. Agents Chemother. May 2012 vol. 56 no. 5 2223-2230. doi: 10.1128/AAC.06288-11 9. Lowrie DB et al. Therapy of tuberculosis in mice by DNA vaccination. Nature. 1999 Jul 15;400(6741):269-71.

Image: Slide culture of Streptomyces sp. Credit: US Centers for Disease Control and Prevention

Natural products from certain bacteria are forming the basis of promising new antimicrobials being developed to tackle drug-resistant infections. Researchers led by Professor Mervyn Bibb at the John Innes Centre1, which receives strategic funding from BBSRC, are studying a group of bacteria called actinomycetes, that produce unique ‘specialised metabolites’. These compounds are not vital to the bacteria’s immediate survival, but can give them a long-term advantage in their natural environment. Many of these specialised metabolites inhibit the growth of rival microbes, and so could potentially be used to develop new human or animal antimicrobials. Fundamental bacterial biology Professor Bibb and his group have been studying a specialised Germany, Denmark, Italy and Switzerland together to develop it The researchers at JIC are interested in the fundamental biology metabolite, which acts as a potent antimicrobial compound, further4. The JIC researchers are helping to increase the amount of of actinomycetes – how natural products such as NAI-107 are called NAI-107 (also known as microbisporicin). It is from a class the lantibiotic produced by the bacteria. “A big issue for pharma made and regulated by the bacteria. However, Professor Bibb is of antimicrobials called ‘lantibiotics’ that are not currently used companies, when they proceed towards clinical trials, is getting also keen to ensure his work is of use to industry, and collaborates clinically, and is produced by the actinomycete Microbispora. enough of the natural product, because often these compounds with researchers from pharmaceutical companies. “We develop a In 2010, the researchers cloned the gene cluster that makes are made in very small amounts,” says Professor Bibb. lot of technology, and fundamental understanding which we feed NAI-107 and developed a comprehensive understanding of how in to pharma and to small biotech companies. Additionally, two the bacteria synthesise the compound and control the amount “By understanding how the gene cluster is regulated we’ve been start-up companies have resulted from work carried out in our that is produced2,3. able to manipulate the natural producer and make group,” he explains. significantly more.” Around the same time, Italian company NAICONS began One of those companies, Novacta Biosystems6, was established in developing NAI-107 commercially. An EU-funded project then NAI-107 is now on the verge of entering phase I clinical trials 2003 based on intellectual property developed by JC researchers brought the company, the JIC researchers, and scientists from to treat MRSA. The market for MRSA therapeutics was estimated studying the lantibiotic cinnamycin, from Streptomyces to be worth around $2.7Bn in 2012, growing to $3.4Bn in 20195. cinnamoneus bacteria. The group, in collaboration with Novacta,

A potent antibiotic “The bad thing is that it also inhibits [a vital biological process developed a method using synthetic biology to construct ‘arti- Professor Bibb is also using synthetic biology to develop called] protein glycosylation in people, so it is toxic.” ficial’ genes to generate variants of cinnamycin7, based on their improved variants of the antibiotic tunicamycin, produced by the understanding of how the bacteria produce and regulate the actinomycete Streptomyces chartreusis10. Working with Professor The aim of the latest project is to use synthetic biology to modify compound8. Novacta adopted this technology to develop and Ben Davis’ group at Oxford, Professor Bibb and colleagues are tunicamycin so that is loses its toxic effects in people while screen around 170 variants of cinnamycin for their antimicrobial investigating whether it is possible to use synthetic biology to retaining its antimicrobial properties11. properties. modify tunicamycin to make it more suitable for use as a human antimicrobial. BBSRC and its predecessors have funded research into the The same technology was later used by Novacta during their biology of the actinomycetes, and in particular a species called in-house programme to develop an antibiotic based on the “It’s a very potent antibiotic,” says Professor Bibb. “The attractive Streptomyces coelicolor, since the 1960s12. Much of this research lantibiotic actagardine, which can be used to treat Clostridium thing from an antimicrobial perspective is that it has a clinically was conducted at JIC, and in 2002 resulted in the first sequence difficile infections. A semi-synthetic variant of actagardine called unexploited target. It targets the production of lipid I, which is of an actinomycete genome; that of S. coelicolor. NVB302 has successfully passed phase I clinical trials and is now used in the production of the bacterial cell wall. No one else has waiting to enter phase II9. used that as a target, so there is no resistance out there in the clinic at the moment.”

References 1. Professor Mervyn Bibb, JIC: https://www.jic.ac.uk/scientists/mervyn-bibb/ 2. Foulston, L. & Bibb, M. (2010). Microbisporicin gene cluster reveals unusual features of lantibiotic biosynthesis in actinomycetes. Proc Natl Acad Sci USA. 107(30):13461-6. doi: 10.1073/pnas.1008285107. 3. Foulston, L. & Bibb, M. (2011). Feed-Forward Regulation of Microbisporicin Biosynthesis in Microbispora coralline. J Bacteriol. 193(12): 3064–3071. doi: 10.1128/JB.00250-11 4. EU Framework Programme 7 project ‘Antibiotic Production: Technology, Optimization and improved Process’: https://www.jic.ac.uk/laptop/about.htm 5. Research and Markets report ‘Methicillin-resistant Staphylococcus aureus (MRSA) Therapeutics - Pipeline Assessment and Market Forecasts to 2019’: http://www.researchandmarkets.com/reports/2152238/methicillinresistant_staphylococcus_aureus 6. Novacta Biosystems: http://www.novactabio.com/ 7. Patent EP1395665A1 ‘Production of the lantibiotic cinnamycin with genes isolated from Streptomyces cinnamoneus.’ https://data.epo.org/gpi/EP1395665A1-PRODUCTION-OF-THE-LANTIBIOTIC-CINNAMYCIN-WITH-GENES- ISOLATED-FROM-STREPTOMYCES-CINNAMONEUS. See also US patent: http://www.google.com/patents/US20040101963 8. Widdick, DA Dodd, H M. Barraille, P White, J Stein, TH Chater, KF Gasson, MJ & Bibb, MJ Cloning and engineering of the cinnamycin biosynthetic gene cluster from Streptomyces cinnamoneus cinnamoneus DSM 40005. Proc Natl Acad Sci USA. 100(7): 4316–4321. doi: 10.1073/pnas.0230516100 9. ‘Novacta Biosystems Limited completes Phase I study of NVB302 against C. difficile infection in healthy volunteers.’ 2012. Available online: http://www.novactabio.com/news.php 10. Wyszynski FJ1, Lee SS, Yabe T, Wang H, Gomez-Escribano JP, Bibb MJ, Lee SJ, Davies GJ, Davis BG. (2012). Biosynthesis of the tunicamycin antibiotics proceeds via unique exo-glycal intermediates. Nat Chem. 4(7), pp539-46. doi: 10.1038/nchem.1351. 11. Current BBSRC grant BB/J006637/1, ‘Understanding and Exploiting Tunicamycin (Bio)Synthesis to Enable Novel Antibiotics and Inhibitors’. Details available online: http://www.bbsrc.ac.uk/pa/grants/AwardDetails.aspx? FundingReference=BB%2fJ006637%2f1 12. BBSRC Impact Case Study ‘Long-term benefits from research into Streptomyces bacteria’. Available online: http://www.bbsrc.ac.uk/publications/impact/streptomyces-bacteria.aspx © Medical Research Council 2014 Antimicrobial resistance Wound dressing provides glowing evidence of infection

Image: The polymers developed by the team incorporate a fluorescent dye and are engineered to recognise and attach to bacteria. The polymers grab the bacteria, shown here as pink fluorescent spots, clumping them together, and then glow blue. Credit: University of Sheffield.

Fundamental research in polymer physics, jointly supported by the Engineering and Physical Sciences Research Council (EPSRC) and Ministry of Defence (MoD), led to the development of wound-healing technology and collaboration between researchers at the University of Sheffield and medical technology company Smith & Nephew Wound Management. Wound dressings which will accurately and quickly detect the presence of bacteria in wounds and help reduce the overuse of antibiotics are being developed.

Bacteria detecting technology From fundamental science to real application When Professors Stephen Rimmer1, Sheila MacNeil2 and Ian detected will alert clinicians to the nature and the severity of Having published papers describing the research in prestigious Douglas3 presented the results of their EPSRC/MoD supported infection. We were the first people to propose this theory.” journals, the team were looking for sponsorship to take the research into branched polymers to military scientists at Porton technology closer to real application when Professor MacNeil Down, it was clear the next stage would be to develop a fast, The team’s work also makes for a much more efficient use of was invited to a national science conference and the team’s work accurate and possibly life-saving technique for detecting the antibiotics. “When the polymer collapses it traps the bacteria started to gain wider public recognition. presence of bacteria in wounds. around it, allowing us to pull the whole thing out without releasing any antibiotics into the wound. This means the bacteria do not Dr Mark Richardson, Vice President of Research and Technology at Professor Rimmer, who heads an interdisciplinary team of polymer develop any antibiotic resistance – which is crucial for patients Smith & Nephew Wound Management4, had been following the scientists, microbiologists and tissue engineers at the university, suffering from chronic wounds who need long-term care,” says team’s work. He says: “We knew the team’s research had been well says: “The polymers we have developed incorporate a fluorescent Professor Douglas. funded; that it was innovative, of the highest quality and of global dye and are engineered to recognise and attach to bacteria, significance for the treatment of wounds. While we would not collapsing around them as they do so. The level of fluorescence normally get involved at the applied research stage, because

Rapid response of the EPSRC funding and the possibility of Technology Strategy The new wound dressings will look very much like Board5 support, we could see the benefits of collaborating with conventional wound dressings, but will contain a hydrogel the Sheffield research team to help develop and build their membrane. A handheld device will be able to detect changes in technologies into some of our existing products.” the colour of the dressing, indicating the presence of bacteria and how best to treat it. With follow-on funding from the Technology Strategy Board, a joint University of Sheffield and Smith & Nephew team is now Providing the clinician and the patient with a tool that alerts them developing the technology that will provide enhanced care for early to a potential infection – and which also reassures them patients suffering from chronic wounds such as diabetic foot when there is no infection – could transform the care of wounds ulcers and venous leg ulcers. and reduce the unnecessary use of antibiotics. By highlighting the presence of an infection at an early stage, it could also help Dr Richardson adds: “Chronic wounds such as these are major prevent wounds becoming colonised by an established layer of health and economic burdens in most developed countries and bacteria (biofilms) which are more resistant to normal antibiotic are primarily wounds of the elderly. With the rise in the levels of treatment and can lead to protracted care. obesity/diabetes this problem can only get worse. These are critical wounds. If they become infected they can be very In the UK alone there are over 200,000 patients suffering from problematic for the patient, in some cases leading to the chronic foot ulcers, with up to 60 per cent of these being amputation of digits or limbs. The early and accurate detection infected. By finding a way of detecting and treating these cases of infection is very important, but at the moment we have no earlier, and more effectively, the team are confident their research point-of-care diagnosis for wounds. Clinicians can take swabs, but will improve patient care and reduce the cost burden on the this can mean a delay of up to 48 hours to get a result, during National Health Service. The aim is to have the new technology which time the patient is potentially at risk.” available commercially within the next four years.

References 1. See https://www.sheffield.ac.uk/chemistry/staff/profiles/stephen_rimmer 2. See https://www.sheffield.ac.uk/materials/staff/smacneil01 3. See https://www.sheffield.ac.uk/dentalschool/about/staff/douglas 4. See http://www.smith-nephew.com/about-us/what-we-do/advanced-wound-management/ 5. The Technology Strategy Board is now called Innovate UK.

Image: Bacteriophage. Credit: BlueSci. Cambridge University science magazine.

With the ever-growing threat of antimicrobial resistance, there is a critical need for alternatives to antibiotics. MRC-funded researchers at the University of Leicester are pursuing one such route. A team led by Dr Martha Clokie has isolated bacteriophages — viruses that ‘eat’ bacteria — targeting the hospital superbug Clostridium difficile or C. difficile.

Bacteriophages were discovered and used as a therapy for stable contaminant-free phage stock. Perhaps the greatest barrier an infection, they are able to clear infections that antibiotics can’t bacterial infections almost 100 years ago, long before the to phage acceptance in the west was the inadequate scientific reach.” Over the past few years, Dr Clokie has isolated and development of antibiotics. Dr Frederick Twort, a British methods used by researchers, such as the exclusion of placebos characterised 40 different phages that infect C. difficile — the bacteriologist and later recipient of MRC funding, is credited with in trials2. With the advent of the antibiotic dawn, phage research largest known set of these phages. Of these, she has developed their initial discovery in 1915. French-Canadian scientist Felix and production were all but shelved, with the exception of Eastern a specific mixture that has proved to be effective against 90 per d’Herelle later developed them to treat infections following his Europe and the former Soviet Union where they continue to be cent of the most clinically relevant C. difficile strains seen in the independent discovery of them in 1917. used therapeutically. UK. The US pharmaceutical company AmpliPhi are funding the further development of these phages, with the aim of testing To date however, they are not in widespread use. Although phages Renewed interest them in Phase I and Phase II trials. This will involve optimising did reach commercial production in the 1940s, and have been Now the threat of widespread antimicrobial resistance has sparked phage preparations for maximum effectiveness against C. difficile used to treat several bacterial infections, treatment does not a renewed interest in phages. Dr Clokie has been studying phages infections and establishing production, storage and delivery produce consistent results. In the pre-antibiotic area, many for 14 years. She says, “As their natural enemy, phages systems for the phage mixture. Dr Clokie will evaluate the aspects of phage biology were not well understood. Doses of specifically target and kill bacteria. They encode a diverse set of effectiveness of the therapy and dosing regimes in collaboration phages often did not contain enough viable viruses to be gene products that can potentially be exploited as novel with Dr Gill Douce at the University of Glasgow. effective, and viruses were used that did not kill the intended antimicrobials. They have the advantage over antibiotics of being bacteria1. There were also problems with the production of a much more specific and, as they can self-replicate at the site of

Dr Clokie says, “The number of bacteriophages that exist on Earth, identify small molecules that mimic the structure and function of combined with their vast genetic diversity and exquisitely specific Gp2 and use these as the basis for new drugs to combat interactions with bacterial hosts means that they have the bacterial infections. potential to offer a real solution for the treatment of a range of human pathogens. A lot of fundamental science needs to Different bacterial infections will require different treatment be carried out in order to ensure that we understand how to best solutions, but it is hopeful that both whole phage particles and exploit them.” their products can be developed as important alternative treatments for human infection. Phage products A potential problem with systemic phage use is the possibility that they may be seen as foreign by the body’s immune system and be destroyed. Delivery of phages also needs to be investigated. To prevent them being damaged by the acidity of the digestive system when ingested, phages would need to be encapsulated or stabilised. A way around these problems might be to use the products of phages rather than the whole organism3.

In 2010, a team of researchers at the MRC Centre for Molecular Bacteriology and Infection (CMBI), also funded by BBSRC, determined the structure of Gp2 — a protein produced by the phage T7 that disables E. coli cells4. In 2012, they demonstrated how Gp2 blocks the action of the bacteria’s RNA polymerase — an enzyme that enables the instructions in the bacteria’s genes to be read and turned into proteins5. The researchers now plan to

References 1. Weld RJ et al. Models of phage growth and their applicability to phage therapy. Journal of Theoretical Biology, Volume 227, Issue 1, 7 March 2004, Pages 1–11. DOI: 10.1016/S0022-5193(03)00262-5 2. Carlton RM. Phage therapy: past history and future prospects. Arch Immunol Ther Exp (Warsz). 1999;47(5):267-74 3. Inal JM. Phage therapy: a reappraisal of bacteriophages as antibiotics. Arch Immunol Ther Exp (Warsz). 2003;51(4):237-44 4. Camara B et al. T7 phage protein Gp2 inhibits the Escherichia coli RNA polymerase by antagonizing stable DNA strand separation near the transcription start site, Proceedings of the National Academy of Sciences of the United States of America. 2010. 107, p 2247-2252 5. E James et al. “Structural and Mechanistic Basis for the Inhibition of Escherichia coli RNA Polymerase by T7 Gp2.” Molecular Cell, 2012.DOI: http://dx.doi.org/10.1016/j.molcel.2012.06.013

Image: Cows on Eefie Hill. Credit: John Comloquoy CC BY-SA 2.0, http://creativecommons.org/ licenses/by-sa/2.0/deed.en

The disease-causing bacterium Staphylococcus aureus, which is carried by and causes serious infections in both humans and livestock, can be transmitted between different host species, providing a source of new infectious strains in people and animals.

The emergence of resistance A widespread pathogen Research led by Professor Ross Fitzgerald1 from the Roslin Institute Antibiotic use is widespread in animal farming, including the S. aureus is a widespread pathogen of humans and of livestock. at the University of Edinburgh, and others, has found that dairy industry and pig farming, as well as in human medicine, so In 2013-14, the NHS reported 826 cases of MRSA infection, and S. aureus has made numerous leaps between host species; from researchers might have expected to see resistance evolving in 9,290 cases of infection by S. aureus susceptible to the antibiotic humans to animals such as dairy cattle and pigs and vice versa. strains of S. aureus present in dairy cattle, as it does in people. methicillin3. S. aureus is also the leading cause of bovine mastitis, In particular, a 2013 study by Professor Fitzgerald and colleagues However, Professor Fitzgerald found that strains of CC97 S. aureus a painful inflammation of the mammary tissue, which costs the showed that a bovine strain called CC97 had made two separate in cattle were not resistant to the antibiotic methicillin. Only once UK dairy industry £200M a year4. The bacteria also cause mastitis leaps to humans2. “There may be a lot more cross-species CC97 strains had crossed to humans and pigs did they acquire in sheep and goats, and various conditions in broiler chickens, transmission than we anticipated,” says Professor Fitzgerald. resistance to methicillin, and further work is needed to including septic arthritis. understand why resistance arose in some strains of the bacteria Following these transmissions, CC97 spread to people on four but not others. As a result, the livestock industry relies on antibiotics to continents over a forty year period. During that time, the strain prevent and treat the infection, which can result in the emergence also acquired resistance to common antibiotics, becoming “There may be something about the pig farming industry that of antimicrobial resistance. Globally, around 70 per cent of methicillin-resistant S. aureus, or MRSA. lends itself to the emergence of antibiotic-resistant strains of antimicrobial use is in farm animals5. S. aureus,” speculates Professor Fitzgerald. “We’ve seen that for The findings suggest that farm animals can provide a ‘reservoir’ several different strains [from pigs] now – they acquire methicillin of S. aureus and MRSA strains that can spread to and cause resistance. We don’t see that to the same level in dairy cows.” disease in human populations.

Almost nine hundred strains Previous studies by Professor Fitzgerald and others found that differences than strains that have only recently evolved from a different strains of S. aureus are associated with different common ancestor. host species, and have become adapted to the conditions those hosts provide. The researchers wanted to understand where the The subsequent development of whole-genome sequencing gave ancestor of these strains came from, and when and how S. aureus researchers a powerful tool to look for genetic changes in the made the leap between host species. entire genome of S. aureus strains. Professor Fitzgerald is now involved in a collaborative project using whole genome sequences To do so, they previously used a technique called ‘multi-locus of almost 900 S. aureus strains. The researchers will study how sequence typing’ to identify genetic changes that had occurred in the bacteria have jumped between hosts across an entire species, the strain at certain locations, or loci, within their genomes. rather than focussing on a single S. aureus strain such as CC97. This could tell the researchers which strains were closely-related They also plan to look at the acquisition of antibiotic resistance and enabled them to estimate when two strains shared a across all of these strains, and whether it is more likely to appear common ancestor. Genetic changes accrue over time, so strains in certain hosts. that have been separated for a long time have more genetic

References 1. Professor Ross Fitzgerald: http://www.roslin.ed.ac.uk/ross-fitzgerald/ 2. Spoor LE, McAdam PR, Weinert LA, Rambaut A, Hasman H, Aarestrup FM, Kearns AM, Larsen AR, Skov RL, Fitzgerald JR. (2013) Livestock origin for a human pandemic clone of community-associated methicillin-resistant Staphylococcus aureus. MBio. 4(4). pii: e00356-13. 3. Public Health England ‘Annual Epidemiological Commentary: Mandatory MRSA, MSSA and E. coli bacteraemia and C. difficile infection data, 2013/14’: http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317141439814 4. “Mastitis is costing the dairy industry £200m a year with the use of antibiotics also increasing year on year, according to National Milk Laboratories’s Hannah Pearse.” Farmers Weekly ‘Dairy Event 2010: Mastitis costs farmers £200m a year’. http://www.fwi.co.uk/articles/08/09/2010/123299/dairy-event-2010-mastitis-costs-farmers-163200m-a.htm 5. POST Note ‘Antibiotic Resistance in the Environment’. (2013) http://www.parliament.uk/business/publications/research/briefing-papers/POST-PN-446/antibiotic-resistance-in-the-environment

Image: Automated DNA sequencing output of human chromosome 1. Credit: Wellcome Images/The Sanger Institute

Following recent improvements in sequencing technologies, whole genome sequencing (WGS) is set to become a crucial tool in the control of antimicrobial resistance1. WGS has already shown considerable promise for the surveillance of infection, the development of new diagnostic tests and the identification of resistance.

Better antimicrobial stewardship Infectious diseases are often transmitted globally. So rapid with conventional methods. The use of WGS confirmed the MRC-funded researchers at the University of Oxford have also detection and identification of outbreaks, and the exchange of outbreak, and also identified a larger population of 26 related used WGS to assess the transmission of fellow superbug information between different authorities and research facilities, cases. Analysis showed that transmission had occurred within the Clostridium difficile (C.difficile)4. Dr David Eyre and Professor Sarah are essential to identify trends and control spread2. WGS could SCBU, between mothers on a post-natal ward, and in the Walker demonstrated that far fewer cases of C. difficile infection have a major part to play in this process. community. WGS data were used to propose and confirm that were transmitted from symptomatic patients than expected, with infection by a staff member had enabled the infection to persist other cases mostly likely coming from asymptomatic individuals or Impact on patient care during periods without known infection on the SCBU and after an environmental source such as water or animals, and food. They Professor Sharon Peacock at the University of Cambridge a deep clean. This individual was successfully treated, after which analysed whole genome sequences of samples obtained from all specialises in the role of sequencing technologies in diagnostic the outbreak ceased. This demonstrated that healthcare and patients with C. difficile infection in Oxfordshire over 3.6 years and microbiology and public health. In 2013 she provided the first community-associated infection should no longer be regarded as found that 45 per cent were sufficiently genetically diverse to evidence that bacterial WGS could be used in clinical practice to separate entities. suggest transmission from sources other than symptomatic impact on patient care3. The infection control team at the study patients. However, the whole genome sequences were also used hospital had identified several infants in a special care baby unit Professor Peacock says, “This study demonstrates that to show that the incidence of cases transmitted from other (SCBU) infected with superbug methicillin-resistant sequencing of microbial pathogens can influence the quality of symptomatic patients and cases from other sources both Staphylococcus aureus (MRSA) over a six-month period. Although infection control and patient care.” declined similarly over the study. These results demonstrate the a link was suspected, a persistent outbreak could not be confirmed importance of interventions to reduce susceptibility to disease in

exposed patients, such as better antimicrobial stewardship, rather cases, potentially leading to early treatment of infectious patients than just reducing transmission from symptomatic patients. They and their contacts. This work has led to whole genome also illustrate the value in combining information from whole sequencing being adopted by Public Health England, initially in a genome sequencing with traditional epidemiology. The use of pilot study within the “100,000 genomes” project, working rapid benchtop sequencing5 again allowed the identification of towards widespread implementation in English tuberculosis genetically related cases in almost real time so that cases clearly reference laboratories from 2016. linked by a hospital or community contact can be targeted to prevent further spread. Professor Peacock has also successfully used WGS to investigate a case of multi drug-resistant (XDR) Mycobacterium tuberculosis8. 100,000 genomes project This proved more accurate than standard methods, with WGS Other MRC-funded researchers in Oxford have also detecting mixed infection by two distinct strains of demonstrated the value of using whole genome sequencing to M.tuberculosis, which was not identified by standard genotyping. investigate clusters of cases of Mycobacterium tuberculosis6,7. This has important implications for distinguishing relapse from Professors Derrick Crook and Tim Peto found that whole genome reinfection and for identifying secondary cases of infection. The sequencing could identify previously unrecognised links between study also highlighted the potential of WGS to predict the cases, more than doubling the number of tuberculosis antimicrobial resistance of M.tuberculosis, which could reduce the transmissions previously identified through standard methods. time taken to implement effective antimicrobial therapy for XDR It was also able to refute the possibility of transmission between M.tuberculosis. This would benefit individual patient care and other cases, saving hours of work trying to work out how could help to contain the spread of infection. transmission could have happened. The technique could also identify super-spreaders and predict the existence of undiagnosed

References 1. Köser CU et al. Whole-genome sequencing to control antimicrobial resistance. Trends in genetics. DOI: 10.1016/j.tig.2014.07.003 2. European Food Safety Authority Scientific Colloquium N°20: Whole Genome Sequencing of food-borne pathogens for public health protection. 3. Harris SR et al. Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study. The Lancet Infectious Diseases Volume 13, Issue 2, February 2013, Pages 130–136 4. Eyre DW et al. Diverse Sources of C. difficile Infection Identified on Whole-Genome Sequencing. N Engl J Med 2013; 369:1195-1205 September 26, 2013 DOI: 10.1056/NEJMoa1216064 5. Eyre DW et al. A pilot study of rapid benchtop sequencing of Staphylococcus aureus and Clostridium difficile for outbreak detection and surveillance. BMJ Open. 2012 Jun 6;2(3). pii: e001124. doi: 10.1136/bmjopen-2012-001124. Print 2012. 6. Walker TM et al. Whole-genome sequencing to delineate M. tuberculosis outbreaks: a retrospective observational study. Lancet Inf Dis 2013 Feb;13(2):137-46. doi: 10.1016/S1473-3099(12)70277-3. 7. Assessment of M. tuberculosis transmission in Oxfordshire, UK, 2007-2012 with whole pathogen genome sequences: an observational study. Lancet Resp Medicine 2014; 2(4):285-92. doi: 10.1016/S2213-2600(14)70027-X 8. Köser CU et al. Whole-Genome Sequencing for Rapid Susceptibility Testing of M. tuberculosis. N Engl J Med 2013; 369:290-292July 18, 2013DOI: 10.1056/NEJMc1215305

Antibiotic class1 Example Class discovered Resistance identified2 Notes Reference

Penicillins Penicillin 1928 1940 First antibiotic, discovered Fleming, A. (1929) On the antibacterial action of cultures of a by Alexander Fleming. Penicillium, with special reference to their use in isolation of B.influenzae. British Journal of Experimental Pathology. 10:226-236.

Abraham, E.P. & Chain, E. (1940). An enzyme from bacteria able to destroy Penicillin. Nature. 146:837

Aminoglycosides Streptomycin 1943 1946 Streptomycin was the ‘Aminoglycoside’. (2014). Encyclopædia Britannica Online. subject of the first ever Retrieved 11 September, 2014, from http://www.britannica.com/ randomised medical trial, EBchecked/topic/20760/aminoglycoside run by the MRC. Crofton, J. (2006). The MRC randomized trial of streptomycin and its legacy: a view from the clinical front line. J R Soc Med. 99; 531. http://jrs.sagepub.com/content/99/10/531.full.pdf+html

Antibiotic class1 Example Class discovered Resistance identified2 Notes Reference

Cephalosporins Cefalexin 1945 Around 1956 Resistance to Turek, M. (1982) Cephalosporins and related antibiotics: an cephalosporins was already overview. Review of Infectious Diseases. 4 (supplement). present in nature when the http://cid.oxfordjournals.org/content/4/Supplement_2/S281.full. antibiotics were developed. pdf This date is based on when researchers identified the Abraham, E.P. &, Newton, G.G. specific enzymes that could 1956. A comparison of the action of penicillinase on break down cephalosporin. benzylpenicillin and cephalosporin N and the competitive inhibition of penicillinase by cephalosporin C. Biochem J. 63(4):628-34.

Tetracyclines Chlortetracycline 1948 1953 Chopra, I & Roberts, M. (2001) Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance. Microbiol. Mol. Biol. Rev. 65 (2), p 232-260. doi: 10.1128/MMBR.65.2.232-260 http://mmbr.asm.org/content/65/2/232.long

Antibiotic class1 Example Class discovered Resistance identified2 Notes Reference

Macrolides Erythromycin 1948 1956 Lewis, K. (2013). Platforms for antibiotic discovery. Nature Reviews Drug Discovery 12, 371–387 doi:10.1038/nrd3975 http://www. nature.com/nrd/journal/v12/n5/fig_tab/nrd3975_T1.html

Leclercq, R. & Courvalin, P. (1991) Bacterial resistance to macrolide, lincosamide and streptogramin antibiotics by target modification. Antimicrob. Agents Chemother. vol. 35 no. 7 1267-1272. doi: 10.1128/AAC.35.7.1267 http://aac.asm.org/content/35/7/1267.full.pdf+html?i- jkey=ae505c6ccf28c31cebad5404d4f64cbf2dab8e6c&key- type2=tf_ipsecsha

Fluoroquinolones Ciprofloxacin 1978 1985 Fluoroquinolones are Crook, S.M., Selkon, J.B. & Mclardy Smith, P.D. (1985) Clinical ‘second generation’ resistance to long-term oral Ciprofloxacin. The Lancet. quinolones introduced in 325 (8440), 1275, doi:10.1016/S0140-6736(85)92343-8 1978. The quinolones were http://www.thelancet.com/journals/lancet/article/PIIS0140- first introduced in 1962, and 6736(85)92343-8/fulltext resistance appeared in 1968.

Glycopeptides Vancomycin 1953 1986 Vancomycin is the current Levine, D.P. (2006) Vancomycin: A History. Clinical Infectious antibiotic of last resort for Diseases. 42:S5–12 Available online: http://cid.oxfordjournals.org/ tackling MRSA infections. content/42/Supplement_1/S5.full.pdf However, vancomycin resistant S. aureus, or VRSA, first appeared in 2002.

1. List is based on NHS classification of antibiotics into six broad groups: http://www.nhs.uk/Conditions/Antibiotics-penicillins/Pages/Introduction.aspx, plus the glycopeptides. 2. Resistance to many naturally-derived antibiotics, for example, penicillin, streptomycin, cephalosporin, existed in nature before the antibiotic was discovered.