Antimicrobial Resistance Timeline Report - MRC

© Medical Research Council 2014

Antimicrobial resistance

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

penicillin growing on a petri-dish of bacteria, antibiotics have

saved the lives of millions of people and animals. Their discovery is

seen as one of the most important scientific achievements of the

20th century. But overuse and misuse of antibiotics has

contributed to the emergence of resistance. Sir Alexander Fleming

himself, on collecting a Nobel Prize for his discovery, predicted the

dawn of this battle, saying, “It is not difficult to make microbes

resistant to penicillin in the laboratory by exposing them to

concentrations not sufficient to kill them…”

England’s Chief Medical Officer Professor Dame Sally Davies

warned in 2013 of the “catastrophic effect” of antimicrobial

resistance and urged immediate action from global leaders before

deaths from routine surgery once again become a common

occurrence1. The World Economic Forum has suggested that

antimicrobial resistance (AMR) be added to the global risk register,

and the World Health Organization has highlighted the serious

implications for global public health in its AMR Global Report on

Surveillance2. Antimicrobial resistance is one of the Innovative

Medicine Initiative’s priorities and a Joint Programming Initiative

on antimicrobial resistance was set up in 2011 to streamline

European research efforts in AMR.

The UK Research Councils support research, capability and training

to pursue a range of strategies to tackle this global problem. Years

of research mean that we are now in a better position than ever to

understand microbes such as bacteria, viruses and fungi, how

they interact with their hosts, and to identify possible routes for

alternative diagnostics and treatments. New technologies which

could help prevent the spread of bacteria and infections, including

smart surfaces and medical dressings, are also being developed.

This timeline and series of case studies showcase some of these

advances, supported by the Biotechnology and Biological

Sciences Research Council (BBSRC), Engineering and Physical

Sciences Research Council (EPSRC) and Medical Research

Council (MRC). This work lays the groundwork for the

cross-Council antimicrobial resistance initiative that was launched

in July 2014. This will see all seven Councils working together to

tackle AMR. A joined-up, multi-disciplinary approach is essential

and so the initiative will coordinate the work of medical

researchers, biologists, engineers, vets, economists, social

scientists, mathematicians and designers. It is only through

tackling the problem at every level and in every environment that

we will be able to take the next steps towards a solution.

References

1. Chief Medical Officer annual report: volume 2

https://www.gov.uk/government/publications/chief-medical-of-

ficer-annual-report-volume-2

2. Antimicrobial resistance: global report on surveillance 2014

http://www.who.int/drugresistance/documents/surveillancereport/en/



1. Understanding resistant bacteria in context of the host

2007: University of Newcastle spin-out company

e-Therapeutics Ltd identifies three

drugs that are effective against

antibiotic-resistant superbugs,

including MRSA, using Grid computing

and e-science techniques developed

during research funded by EPSRC and the

Department of Trade and Industry1. The

company searched through tens of

millions of compounds for any that

showed action against superbugs in a

fraction of the time it would take using

conventional drug discovery methods.

2008: The first case of a bacterial infection with

resistance caused by NDM-1, a powerful

enzyme that gives bacteria resistance

to most antibiotics, is discovered2.

MRC-funded researcher Professor Tim

Walsh was part of the group that

identified the enzyme, which is commonly

produced by Escherichia coli and Klebsiella

pneumonia, but can also spread

between different strains of bacteria.

2010: The EU uses the results of research by

BBSRC David Phillips Fellow Dr Mark

Webber in two reports on the use of

common biocides3. During his fellowship,

Dr Webber characterised the genetic

changes that grant Salmonella resistance

to the biocide triclosan and others4. There

were around 9,000 cases of Salmonella

food poisoning in the UK in 2010,

although three quarters of cases may

go unreported5.

BBSRC-funded researchers find a protein

on the surface of Streptococcus uberis

bacteria, responsible for bovine mastitis,

which plays a central role in enabling the

bacteria to cause disease6. The findings

suggest it may be possible to develop

a vaccine against the disease, reducing

farmers’ reliance on antibiotics.

2011:Scientists at the MRC Research

Complex at Harwell determine the

structure of NDM-1 using the STFC’s

Diamond Light Source crystallography

facility7. Understanding the structure

will help researchers develop drugs that

could inactivate the enzyme or that

are not susceptible to it.

Professor Hagan Bayley at the University

of Oxford discovers that the antibiotic-

resistance of Escherichia coli is not due to

the reduced size of OmpC — the channel

in the bacteria’s membrane that allows

the entry of antibiotics — as is the cause

of much resistance, but a change in its

electrostatic field8.

2012: The gene which grants one strain of MRSA

found in hospitals resistance to a range

of antibiotics also reduces the bacteria’s

ability to secrete the toxins that

cause illness, according to a BBSRC and

MRC-funded study led by Dr Ruth Massey

at the University of Bath9. The results also

highlight the problem of

‘community-acquired’ MRSA strains, which

can both resist antibiotics by making

changes to the bacterial cell wall and

maintain high levels of toxin production.

Dr Andrew Edward at the MRC Centre

for Molecular Bacteriology and Infection

(CMBI), Imperial College London,

demonstrates that Staphylococcus aureus

changes from its normal form to a

slow-growing antibiotic-resistant form

as part of its natural lifestyle to ensure

its survival10.

Bacteria transmit resistance genes to

other bacterial strains by way of

plasmids — small loops of DNA. Carrying

these plasmids is commonly thought to

reduce a bacterium’s fitness, so removal

of antibiotic pressure should reduce the

number of resistant bacteria. However, in

a BBSRC and MRC-funded study, Professor

Laura Piddock and Dr Mark Webber at the

University of Birmingham discover that

the plasmid pCT persists in the absence of

antibiotics because it has evolved to have

little impact on the host11. They conclude

that resistance genes will persist even with

careful rationing of antibiotics.



In an MRC-funded study, Professor Gad

Frankel at Imperial College London uses a

mouse infected with bacteria genetically

modified to produce light to show how an

infection moves around the body in real

time12 & 13. Regular CT scans of the mouse

could show how different vaccines and

antibiotics change the way bacteria take

over parts of the body.

2013: A research team from the Universities of

Nottingham, Birmingham and Newcastle,

funded by EPSRC and BBSRC, discover

that artificial materials based on simple

synthetic polymers can disrupt the way in

which bacteria communicate with each

other. The findings14 open up the

possibility to influence microbial

behaviour by controlling their ability to

form productive communities, which

could be exploited to prevent the release

of toxins during the spread of infection.

A common mutation in Salmonella grants

the bacteria resistance to an important

class of antibiotics, the fluoroquinolones,

and also increases its resistance to many

other antibiotics and the biocide triclosan,

according to research by Professor Laura

Piddock and Dr Mark Webber at the

University of Birmingham15 and supported

by BBSRC and the MRC.

MRC-funded Professor Guy Frankel

at Imperial College shows how

enteropathogenic Escherichia coli (EPEC),

a pathogenic strain of E.coli which is a

common cause of infant diarrhoea in the

developing world, interferes with the host

cell’s normal antimicrobial response16.

EPEC injects a toxin into host cells during

infection. This blocks the cell’s ability to

send messages to the immune cells,

preventing a response and subsequent

death of the infected cells, allowing the

bacteria to survive and spread.

BBSRC-funded researchers at the

University of Cambridge find the gene

responsible for activating the infection

mechanism in Pseudomonas aeruginosa

when the bacteria encounter low oxygen

conditions, such as those found in the

lungs of people with severe respiratory

illnesses, including cystic fibrosis17.

P. aeruginosa infection is one of the most

common causes of death in cystic

fibrosis patients.

2014: BBSRC-funded researchers at the MRC

Centre for Molecular and Biomolecular

Informatics (CMBI), identify the pathway

behind the ‘stringent response’, the

mechanism E.coli use to survive when

under stress, such as when deprived of

nutrients or in the presence of

antibiotics18. When under stress, bacteria

produce guanosine tetraphosphate

(ppGpp), which instructs the bacteria to

stop growing and to use minimal

resources. The CMBI researchers

show that a protein called NtrC plays a

central role in the process by controlling

the level of ppGpp.

Researchers at the London Centre for

Nanotechnology, University College

London, show how drug-binding

mechanically weakens bacterial cells

and leads to their death, whilst unravelling

how the antibiotic vancomycin works.

Vancomycin is one of the few effective

treatments for MRSA. The study was

funded by EPSRC, BBSRC and the

Royal Society.

Researchers at the MRC Centre for

Molecular Bacteriology and Infection

(CMBI) study ‘persister’ cells in Salmonella,

visualising them for the first time using a

fluorescent protein produced by the

bacteria. Persister cells are a non-

replicating form of the bacteria and

‘lie low’ to evade antibiotic action19.

See ‘Antibiotic-evading bacteria’.

Professor Laura Piddock at the University

of Birmingham sequences the plasmid

pCT, which confers antibiotic resistance

to bacteria carrying it. She concludes that

the plasmid’s success lies in its stability

in a range of hosts, the lack of a fitness

cost to the host bacteria — meaning that

carrying the plasmid has no detrimental

effect — and efficient transfer between

bacterial hosts20.



2. Accelerating therapeutic and diagnostics development

1985: Researchers at the John Innes Centre (JIC),

which receives strategic funding from

BBSRC, led by Dr David Hopwood, are the

first to produce a ‘hybrid’ antibiotic using

genetic engineering, alongside colleagues

from Japan and the USA21. The researchers

transferred genes associated with

antibiotic production between strains

of Streptomyces bacteria, enabling the

bacteria to produce an entirely new

antimicrobial compound.

1998: Professor Jeff Errington founds spin-out

company Prolysis to develop and

commercialise screening techniques to

find novel antibiotics to tackle drug-

resistant bacterial infections22. The

company is based on fundamental

bacterial cell biology research supported

by BBSRC at the University of Oxford. In

2009 Prolysis is acquired by Australian

drug development firm Biota.

2002: The Streptomyces genome, sequenced

by BBSRC- and Wellcome Trust-funded

researchers, is published in the journal

Nature23. Researchers subsequently

discover a large number of previously-

unknown gene clusters in the

Streptomyces genome that produce

‘specialised metabolites’, potentially

including previously-unknown

antimicrobials.

2003: JIC spin-out company Novacta

Biosystems24 is founded to discover and

develop potential treatments for

infectious diseases, particularly those

caused by antimicrobial-resistant bacteria.

Their lead product, based on a long

history of Streptomyces research at JIC25,

is designed to treat infections caused by

the bacterium Clostridium difficile;

which was involved in 2,704 deaths in the

UK in 201026. See ‘New antibiotics from

bacterial bioscience’.

2005: Dr Curtis Dobson founds spin-out

company Ai2 to develop an anti-infective

coating for contact lenses. The anti-

infective arose from Dr Dobson’s

BBSRC-funded research at the University

of Manchester into a protein that could

help protect against the viral infections

associated with Alzheimer’s disease27.

2007: Professor Simon Foster and Dr Jorge

Garcia-Lara at the University of Sheffield

create spin-out company Absynth

Biologics to develop vaccines against S.

aureus infection, including MRSA28.

Absynth arose from Professor Foster’s

BBSRC and MRC-funded research into S.

aureus, and in particular the genes

essential for its survival.

The company has since identified two

promising protein targets for use in

vaccines.

Demuris, Professor Jeff Errington’s second

spin-out company, is founded, based on

BBSRC-funded research. The company is

using a unique collection of actinomycete

bacteria, together with Professor

Errington’s understanding of bacterial cell

biology, to look for potentially valuable

new natural products, including

antibiotics29.

2008: Procarta Biosystems is co-founded by

Professor Mervyn Bibb and Dr Michael

McArthur at JIC to develop and

commercialise a new class of antibiotics,

DNA-based transcription factor decoys

(TFDs), to combat infections caused by

drug-resistant bacteria30. TFDs work by

blocking the action of ‘transcription

factor’ proteins that control the

expression of large numbers of genes

within the bacterial cells.

2009: Professor Jeremy Lakey co-founds

spin-out company OJ-Bio, based on

BBSRC-funded research at Newcastle

University, to develop miniature wireless

sensors that can be used to test for a

diverse range of infectious diseases in

humans31. The devices are currently being

evaluated by commercial partners in the

healthcare industry to test for infectious

diseases including flu, HIV and gum

disease. Further funding has been

provided by the EPSRC and Technology

Strategy Board (now Innovate UK) to

develop the technology.



MRC and BBSRC-funded researcher

Professor Adam Cunningham at the

Universityof Birmingham begins

development of a vaccine against

Salmonella32. The vaccine development

has been licensed to Novartis Vaccines

Institute for Global Health.

2010: A team of researchers at the MRC Centre

for Molecular Bacteriology and Infection

(CMBI), with funding from BBSRC, reveal

the structure of a protein called Gp2,

produced by the ‘bacteriophage’ virus T7,

which disables E.coli cells33. Bacteriophage

viruses infect and kill many bacterial

species, including those that cause

human and animal diseases. See

‘Bacteria-eating viruses’.

Ai2, the spin-out company established by

Dr Dobson at the University of

Manchester, announces a multimillion

pound licencing deal with UK-based

contact lens and aftercare manufacturer

Sauflon to use the anti-infective coating

in their products34.

Researchers at the MRC Laboratories in

The Gambia, in collaboration with

scientists in the US, find that infection

with H.pylori – the bacterium

responsible for gastritis and gastric ulcers

– may protect the host against other

pathogens, such as tuberculosis35.

2011: A Sheffield University research team

produce a gel containing molecules that

bind to bacteria and activate a

fluorescent dye. The gel will be used in

wound dressings to indicate when an

infection has developed and will help

clinicians to make rapid, informed

decisions about wound management as

well as reduce the overuse of antibiotics.

The research team was funded by the

EPSRC and Ministry of Defence. See

‘Wound dressing provides glowing

evidence of infection’.

Funded by the MRC, Dr Andrew Gorringe

at the Health Protection Agency develops

a vaccine against bacterial meningitis.

The vaccine is currently being developed

with funding from the Biomedical Catalyst

by ImmBio, a vaccine development

company based at the Babraham

Research Campus36.

BBSRC-funded researchers begin to

develop a new type of vaccine to protect

chickens against coccidiosis37, based on a

single protein that plays a vital role in the

early stages of infection. The coccidiosis

parasite, which is widely resistant to

antimicrobials, is the most important

parasite of poultry globally.

Predatory bacteria with the potential

to be used as ‘living antibiotics’ are safe

when ingested by chickens, according to

BBSRC-funded researchers from the

University of Nottingham38. When given

to live, Salmonella-infected chickens,

Bdellovibrio bacteria reduced the number

of Salmonella cells by 90 per cent while

leaving the birds unharmed.

Researchers are using synthetic biology

approaches to alter antibiotic production

in marine bacteria to produce new hybrid

antibiotics39. The BBSRC- and EPSRC-

funded researchers, from the University

of Birmingham and working with others in

the UK and Japan, found that the marine

bacteria could combine two antibiotic

molecules to produce a much more

effective antibiotic, which works

against MRSA.

Scientists at the Institute of Food

Research (IFR), which receives strategic

funding from BBSRC, adapt the structure

of the protein endolysin, derived from

a bacteriophage virus, so that it is more

effective against C. difficile, a common

cause of hospital-acquired infections,

while remaining ineffective against

beneficial gut bacteria40.

2012: BBSRC-funded researchers at the MRC

Centre for Molecular Bacteriology and

Infection (CMBI) demonstrate how Gp2

interacts with the bacteria’s RNA

polymerase — an enzyme that enables

the instructions in the bacteria’s genes to

be read and turned into proteins —

to stop it from functioning41. The

scientists now plan to identify small


Antimicrobial resistanceAntimicrobial resistance

molecules that mimic the structure and

function of Gp2 and use these as the

basis for new drugs to combat

bacterial infections.

Novacta Biosystem’s lead product,

NVB302, which is being developed to treat

C. difficile infections, completes phase

I clinical trials, showing it is safe when

administered to healthy people42.

JIC and University of Oxford researchers

begin a BBSRC-funded project to

investigate whether they can use

synthetic biology to remove the toxic

side effects of tunicamycin; an antibiotic

produced by the soil bacterium

Streptomyces43. See ‘New antibiotics from

bacterial bioscience’.

MRC-funded researchers at the Wellcome

Trust Sanger Institute demonstrate that

treatment of C. difficile-infected mice

with faeces from healthy mice rapidly

restores a diverse, healthy microbiota

and subsequently cures the disease and

removes its contagiousness44.

MRC-funded researcher Professor Robert

Akid at the University of Manchester

patents an antimicrobial coating for

cementless prostheses, such as hip and

knee replacements, to prevent infection45.

The controlled release ensures the

antimicrobial is released only at the

appropriate time (during and

after surgery).

2013:An EPSRC Interdisciplinary Research

Centre46 is established at University

College London to create a new

generation of early-warning sensing

systems to diagnose, track and prevent

the spread of infections, including

influenza, antimicrobial resistance and

HIV, using mobile communication,

nanotechnology, genomics and big data

analysis to actively manage outbreaks and

prevent infectious diseases.

The world’s largest antibody search

engine, CiteAb47, is founded by

EPSRC-funded Dr Andrew Chalmers at the

University of Bath. The service, which

allows researchers to find antibodies for

use in their research, is the largest

antibody search engine in a $2Bn antibody

industry, and ranked number one by

Google. Ranking antibodies by academic

citations means CiteAb provides an

independent, verifiable guide as to

whether an antibody is likely to work in

the laboratory, saving both time

and money.

Absynth Biologics receives more than £2M

through the Technology Strategy

Board- and MRC-funded Biomedical

Catalyst to take forward to a pre-clinical

stage its vaccine against MRSA.

A team led by MRC-funded researcher

Dr Martha Clokie at the University of

Leicester isolates 40 different

bacteriophages — viruses that ‘eat’

bacteria — against hospital superbug C.

difficile. US pharmaceutical company

AmpliPhi Biosciences Corporation are

funding the further development of these

phages. See ‘Bacteria-eating viruses’.

2014: Imperial College London scientists, with

support from BBSRC, identify how a

protein, called P7, produced by a certain

bacteriophage virus disables an essential

bacterial enzyme called RNA

polymerase48. The viral protein uses a

previously-unknown method to disable

the RNA polymerase, which is involved

in bacterial gene expression, by preventing

it from identifying target genes.



2007: A peptide molecule found in American

Bullfrogs is being developed to treat

wounds infected with MRSA49. Researchers

led by Dr Peter Coote at the University of

St Andrews find that the bullfrog peptide

ranalexin can inhibit MRSA growth when

combined with another antimicrobial,

lysostaphin. The researchers patent the

discovery and aim to develop effective

treatments for MRSA-infected wounds.

2010: Bacteria carried on the surface of

leafcutter ants produce a range of

antimicrobial compounds, according to a

study by BBSRC and MRC-funded

researchers from the University of East

Anglia, JIC, and The Genome Analysis

Centre (TGAC), which receives strategic

funding from BBSRC50. The antimicrobials

help the ants cultivate a

fungus that provides them

with food, protecting their nest against

infection and controlling competing

strains of fungi51.

2011: Materials scientists at the University of

Birmingham, funded by EPSRC, devise a

way of making stainless steel surfaces

resistant to bacteria by introducing silver

or copper into the surface rather than

applying it as a coating. The technique

could prevent the spread of superbug

infections on stainless steel surfaces in

hospitals as well as medical equipment

such as instruments and implants, the

food industry, and domestic kitchens.

2012: Researchers at the University of

Nottingham, funded by BBSRC and the

Wellcome Trust, discover a new class of

material that resists colonisation by

bacteria52. The materials, known as

synthetic acrylate polymers, have been

licensed to UK company Camstent Ltd,

which is now working with the academics

to develop coated urinary catheters.

In an MRC-funded study, Professor

Timothy Walsh sequences K. pneumonia

containing NDM-1 from three different

countries and shows that there is great

diversity between the strains. He finds

that one of the most common strains,

ST14, is associated with the most invasive

form of the disease53.

2013: EPSRC-funded researchers develop a

method for quickly detecting infections in

children with serious burns54. Children are

at higher risk than adults from the effects

of subsequent infection. The dressing,

developed at the University of Bath with

researchers from Bristol’s Frenchay

hospital and Bedfordshire based

AmpliPhi Biosciences, uses dye-filled

nanocapsules that burst open in the

presence of disease-causing bacteria.

Using a UV light, clinicians can quickly

check whether there is any infection by

seeing if the dressing lights up.

Researchers at the University of Sheffield

discover that combinations of bacteria,

commonly found in water pipes, can form

a ‘biofilm’ that enables other, potentially

harmful, bacteria to thrive55. The

EPSRC-funded study isolated four types of

bacteria and found that when any of them

grew alongside bacteria called

Methylobacterium, they formed a biofilm

within 72 hours. The findings mean it

should be possible to control the creation

of biofilms in water supplies by targeting

particular bacteria.

Researchers at the University of Warwick

adopt a DNA-based approach to under

stand the community of microbes that

live in a chicken’s gut56. Chickens and other

farm animals can act as a reservoir of

human pathogens and of microbes that

carry antimicrobial resistance genes. The

researchers, with support from BBSRC,

used high-throughput sequencing to

rapidly sequence the DNA of microbes in

the chicken gut to identify which bacterial

species were present.

Some strains of MRSA that cause disease

in humans originate in livestock,

according to research led by Professor

Ross Fitzgerald at the Roslin Institute,

which receives strategic funding from

BBSRC57. The findings suggest that

livestock can act as a potential reservoir

of new human epidemic strains of the

bacteria. See ‘Making the leap’.

3. Understanding the real world interactions



MRC-funded Professor Sharon Peacock

at the University of Cambridge uses

whole-genome sequencing to analyse

an outbreak of MRSA58. Whole genome

sequencing of bacterial samples could

lead to fewer antibiotics being used as

a more specific diagnosis would allow

the targeted use of specific antibiotics

to treat it. This sequencing also means

that researchers can track the spread of

infection, helping with infection control

and prevention. See ‘Whole-genome

sequencing’.

The Chief Medical Officer publishes the

second volume of her annual report,

focusing on infection and antimicrobial

resistance. Professor Peacock writes a

section on the use of whole genome

sequencing to track the transmission of

infections to improve surveillance

and control59.

An MRC-funded team at the University of

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’.



4. Behaviour within and beyond the health care setting

2005: With up to 50 per cent of antibiotic

prescribing inappropriate61, Professor Peter

Davey at the University of Dundee looks

at interventions to improve prescribing,

such as education, restriction of drugs,

guideline implementation and expert

approval in an MRC-funded study62.

2007: In an MRC-funded study, Professor David

Mant at the University of Oxford shows

that antibiotic-resistant bacteria are

present in children prescribed the

common antibiotic amoxicillin, which

although transitory in the children is

sufficient to sustain a high-level of

antibiotic resistance in the population63.

The findings provide clinicians with

guidance on which

antibiotics should be used if a patient

requires a second course of antibiotics

within 12 weeks of the first.

It was previously thought that using less

active antibiotics was the best first

defence in order to reserve more active

antibiotics for more resilient bacteria. In

an MRC-funded study, Professor Sebastian

Amyes at the University of Edinburgh

concludes that using less active antibiotics

first — which are generally more likely to

cause resistance to develop — results

in resistance to the whole class of

antibiotics, rendering even the more

active types unusable64.

2011: Pigs on farms with access to the outdoors

and a clean, enriched environment are

less likely to suffer Post Weaning

Multi-systemic Wasting Syndrome

(PWMS), which is associated with a certain

virus, than those on other farms,

according to BBSRC-funded researchers

from the Royal Veterinary College65.

The researchers are now working with

the British Pig Executive to develop

monitoring systems to help farmers

identify animals at risk of PWMS.

The Imperial Antibiotic Prescribing Policy

(IAPP) smartphone app is developed by

Imperial College Healthcare NHS Trust’s

antibiotic review group and the UKCRC

Centre for Infection Prevention and

Management66. The app helps healthcare

professionals choose the most

appropriate course of treatment to

ensure antimicrobials are prescribed

appropriately. The app is used over 4,800

times in the first month. 85 per cent

of users responding to a post-

implementation survey considered

that the IAPP added to their knowledge

base regarding antimicrobial prescribing

and 96 per cent found that it influenced

their prescribing practice.

Professor Ian Chopra, director of the

Antimicrobial Research Centre at the

University of Leeds advocates that new

business models for antibiotic

development are required. He suggests

new methods of screening for

compounds, delinking product sales

from the companies’ return on investment

and financing incentives for

drug development67.

2012: EPSRC-funded researchers at the

University of Leeds discover that

superbugs, such as MRSA and C. difficile,

not only spread through contact, but they

also float on air currents and contaminate

surfaces far from infected patients’ beds68.

Coughing, sneezing or shaking bedclothes

can send superbugs into the air, allowing

them to contaminate recently cleaned

surfaces. This may explain why,

despite strict cleaning regimes and

hygiene controls, some hospitals still

struggle to prevent bacteria moving

from patient to patient.

2013: The Joint Programming Initiative on

Antimicrobial Resistance publishes its

Strategic Research Agenda69. MRC-funded

Professors Tim Walsh and Paul Williams

were involved in its development.

2014: An international team of researchers,

including MRC-funded researcher

Dr Tim Felton, recommend individualised

antibiotic dosing for critically-ill patients70.

These patients often exhibit different

responses to antibiotic treatment; dosing

that does not take this into consideration

can lead to sub-optimal treatment and

increase antibiotic resistance.



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.



References1. e-Therapeutics plc press release: ‘Successful completion of preclinical efficacy and resistance studies of candidate antibiotic ETX1153 against MRSA http://etherapeutics.co.uk/userfiles/file/Preclinical%20update%20FINAL%20101207c.

pdf?phpMyAdmin=4bfc4f2a6615t34ee8c43r5826

2. Yong D et al (2009). Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India.

Antimicrob Agents Chemother. 2009 Dec; 53(12):5046-54. doi: 10.1128/AAC.00774-09.

3. http://www.bbsrc.ac.uk/publications/impact/david-phillips-fellowships.aspx

4. Webber, MA, Randall, LP, Cooles, S, Woodward, MJ., & Piddock, LJ (2008) Triclosan resistance in Salmonella enterica serovar Typhimurium. J. Antimicrob. Chemother. 62 (1): 83-91. doi: 10.1093/jac/dkn137

5. Salmonella data: http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/Salmonella/EpidemiologicalData/salmDataHumanMonth/ and https://www.gov.uk/government/uploads/system/uploads/attachment_data/

file/69313/pb13571-zoonoses2009-110125.pdf

6. Leigh JA, Egan SA, Ward PN, Field TR, & Coffey TJ. (2010). Sortase anchored proteins of Streptococcus uberis play major roles in the pathogenesis of bovine mastitis in dairy cattle. Vet. Res. 41(5): 63. doi: 10.1051/vetres/2010036.

7. Green VL et al (2011). Structure of New Delhi metallo-ß-lactamase 1 (NDM-1). Acta Cryst. (2011). F67, 1160-1164 doi:10.1107/S1744309111029654

8. Lou H et al (2011). Altered Antibiotic Transport in OmpC Mutants Isolated from a Series of Clinical Strains of Multi-Drug Resistant E. coli. PLoS One. 2011;6(10):e25825. doi: 10.1371/journal.pone.0025825. Epub 2011 Oct 28.

9. Rudkin, JK, Edwards, AM, Bowden, MG, Brown, EL, Pozzi, C, Waters, EM, Chan, WC, Williams, P, O’Gara, JP and Massey, R C, (2012). Methicillin Resistance Reduces the Virulence of Healthcare-Associated Methicillin-Resistant

Staphylococcus aureus by Interfering With the agr Quorum Sensing System. Journal of Infectious Diseases, 205 (5), pp. 798-806.

10.Edwards AM (2012). Phenotype switching is a natural consequence of Staphylococcus aureus replication. J Bacteriol. 2012 Oct;194(19):5404-12. doi: 10.1128/JB.00948-12. Epub 2012 Aug 3.

11. Cottell JL et al. (2012) Persistence of transferable extended-spectrum-ß-lactamase resistance in the absence of antibiotic pressure. Antimicrob Agents Chemother. 2012 Sep;56(9):4703-6. doi: 10.1128/AAC.00848-12. Epub 2012 Jun 18.

12. Collins JW et al (2013). 4D multimodality imaging of Citrobacter rodentium infections in mice. J Vis Exp. 2013 Aug 13;(78). doi: 10.3791/50450.

13. http://www.bbc.co.uk/news/health-18631157.

14. Lui LT, Xue X, Sui C, Brown A, Pritchard DI, Halliday N, Winzer K, Howdle SM, Fernandez-Trillo F, Krasnogor N, Alexander C. (2013). Bacteria clustering by polymers induces the expression of quorum-sensing-controlled phenotypes.

Nature Chemistry. 5, 1058-1065 doi:10.1038/nchem.1793.

15. Webber, MA, Ricci, V, Whitehead, R, Patel, M, Fookes, M, Ivens, A, & Piddock, L (2013). Clinically relevant mutant DNA gyrase alters supercoiling, changes the transcriptome and confers multi-drug resistance. mBio. 4(4),

e00273-13. doi: 10.1128/mBio.00273-13.

16. Pearson JS et al (2013). A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature 501, 247–251(12 September 2013) doi:10.1038/nature12524.

17. Chung, JC, Rzhepishevska, O, Ramstedt, M, & Welch, M (2013). Type III secretion system expression in oxygen-limited Pseudomonas aeruginosa cultures is stimulated by isocitrate lyase activity. Open Biol. 3(1): 120131. doi: 10.1098/rsob.120131.

18. Brown, DR et al (2014). Nitrogen stress response and stringent response are coupled in Escherichia coli. Nat. Commun. 5:4115 doi: 10.1038/ncomms5115 (2014).

19. Helaine, S et al (2014). ‘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.

20. Cottell JL et al (2014). Functional genomics to identify the factors contributing to successful persistence and global spread of an antibiotic resistance plasmid. BMC Microbiology 2014, 14:168 doi:10.1186/1471-2180-14-168.

21. Hopwood DA, Malpartida F, Kieser HM, Ikeda H, Duncan J, Fujii I, Rudd BA, Floss HG, Omura S. (1985). Production of ‘hybrid’ antibiotics by genetic engineering. Nature. 314(6012):642-4.

22. See full details at: http://www.bbsrc.ac.uk/publications/impact/prolysis-demuris.aspx

23. Bentley SD1, Chater KF, Cerdeño-Tárraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D, Bateman A, Brown S, Chandra G, Chen CW, Collins M, Cronin A, Fraser A, Goble A, Hidalgo J, Hornsby

T, Howarth S, Huang CH, Kieser T, Larke L, Murphy L, Oliver K, O’Neil S, Rabbinowitsch E, Rajandream MA, Rutherford K, Rutter S, Seeger K, Saunders D, Sharp S, Squares R, Squares S, Taylor K, Warren T, Wietzorrek A, Woodward J,

Barrell BG, Parkhill J, Hopwood DA. (2002). Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature. 417(6885). pp141-7.



References24. 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.



References52. 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 <http://creativecommons.org/licenses/by/3.0/>

Understanding resistant bacteria in context of the host Image 1: Salmonella invading cultured human cells. Credit: NIAID. CC BY 2.0 <https://creativecommons.org/licenses/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 <http://creativecommons.org/licenses/by/2.0/deed.en>

Accelerating therapeutic and diagnostics developmentImage 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 <https://creativecommons.org/licenses/by/2.0/>

Image 6: The connectedness of today’s society. Credit: Thinkstock.

Understanding the real world interactionsImage 1: American Bullfrog Rana catesbeiana. Credit: Fir0002. CC BY-SA 2.5 <http://creativecommons.org/licenses/by-sa/2.5/deed.en>

Image 2: Surgical instruments. Credit: Thinkstock

Image 3: Cows on Eifee Hill. Credit: John Comloquoy CC BY-SA 2.0 <http://creativecommons.org/licenses/by-sa/2.0/deed.en>

Image 4: Automated DNA sequencing output of human chromosome 1. Credit: Wellcome Images/The Sanger Institute.

Behaviour within and beyond the healthcare settingImage 1: Pigs. Credit: Hadyn Blackey. CC BY-SA 2.0 <http://creativecommons.org/licenses/by-sa/2.0/deed.en>

Image 2: The Imperial Antibiotic Prescribing Policy smartphone app. Credit: 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.

Antibiotic-evading bacteria

Most antibiotics act only on active bacteria. But nearly all bacterial

pathogens produce a small sub-population of dormant cells that

can evade antibiotics. These cells — called persisters — tolerate

antibiotics and other environmental stresses, such as nutrient

depletion or host cell acidity. Once the stress has been removed,

for example, by the completion of a course of antibiotics, the

dormant cells are able to revert back to the active, disease-causing

form. These cells are thought to be the cause of many persistent

or recurrent infections.

This antibiotic ‘tolerance’ is temporary and reversible, unlike

resistance, which is caused when the bacteria acquire stable

genetic traits. However, it is thought that prolonged and

repeated treatment of persistent infections may lead to

genetic drug resistance1, and so it is important that the

mechanisms behind this evasion are identified to help develop

appropriate strategies to treat these persisters. Despite their

discovery by Joseph Biggar more than 70 years ago2, persister

cells are still poorly understood.

Persisters and resistance

Up until now, persister cells have only been studied in test tubes.

However, in 2014, a team led by Professor David Holden at the

CMBI used a technique they had developed to visualise persisters

for the first time at the single-cell level as they are consumed by

white blood cells3.

Using a fluorescent protein, Professor Holden and colleagues

showed that the bacteria produced persister cells when consumed

by white blood cells at a much greater rate than when grown in

laboratory media. The researchers demonstrated that the bacteria

formed persisters immediately after being attacked and

consumed by the host’s white blood cells in response to the levels

of acidity and lack of nutrients inside the cells.

These stresses also cause some bacterial cells to start replicating

rather than form persister cells, and this dual response allows

bacteria to ‘hedge their bets’ to gives them a selective advantage.

Professor Holden is now hoping to use these approaches to study

how persister cells might lead to resistance.

“It is widely thought that the multiple courses of antibiotics made

necessary by persistent infections leads to resistance. However,

this has not been tested experimentally. Since the genetic basis of

persister formation has been worked out in recent years, we

Image: Salmonella coloured green growing in macrophages.

Credit: MRC Centre for Molecular Bacteriology and Infection,

Imperial College London.



can make bacterial mutants with enhanced or reduced persister

frequency and use these in conjunction with our techniques

to determine if and how persisters contribute to emergence of

resistance during infection,” says Professor Holden.

Surviving adverse conditions

Part of Professor Michael Barer’s research at the University of

Leicester looks at the transmission and persistence of

Mycobacterium tuberculosis. In 2008 he, together with colleagues

at the MRC unit, The Gambia, demonstrated that the tuberculosis

bacteria in samples of sputum — the mucus and other matter

brought up from the lungs by coughing, and which helps transmit

the disease between people — were likely to be in their persistent

state. These samples contained a fat called triglyceride, produced

by the bacteria when they form persister cells. This suggests that

formation of the persisters might help the bacteria survive the

adverse conditions that M. tuberculosis encounters when it

is transmitted between people4.

Targeting persistersPyrazinamide is the only drug that specifically targets persister

cells. In 1970 researchers at the MRC Tuberculosis and Chest

Diseases Unit5 demonstrated for the first time that the inclusion

of pyrazinamide in an antibiotic regimen for the treatment of

Mycobacterium tuberculosis substantially reduced the relapse

rate6. Certain antibiotics however do have limited action against

the persisters and REMoxTB, a clinical trial involving several MRC

researchers, is currently underway to determine whether the

inclusion of the antibiotic moxifloxacin can shorten the duration

of treatment7.

Enhancing the host’s immune response is another method of

targeting persister cells8. The bacillus Calmette-Guerin (BCG)

vaccine has limited success as a preventative measure. However,

researchers at the MRC’s National Institute of Medical Research

(NIMR) showed that the use of the M. tuberculosis Hsp60 DNA

vaccine, in combination with antibacterial treatment, was

successful in treating heavily infected mice. The DNA vaccinations

can switch the immune response from one that is relatively

inefficient to one that kills these persistent bacteria9.

“Another possibility is to work out what triggers the persister

cells to start growing again — give someone with a persistent

infection a drug that induces this — and then attack the bacteria

as they come out of hiding,” says Professor Holden.

References1. 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.



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.

New antibiotics from bacterial bioscience

Professor Bibb and his group have been studying a specialised

metabolite, which acts as a potent antimicrobial compound,

called NAI-107 (also known as microbisporicin). It is from a class

of antimicrobials called ‘lantibiotics’ that are not currently used

clinically, and is produced by the actinomycete Microbispora.

In 2010, the researchers cloned the gene cluster that makes

NAI-107 and developed a comprehensive understanding of how

the bacteria synthesise the compound and control the amount

that is produced2,3.

Around the same time, Italian company NAICONS began

developing NAI-107 commercially. An EU-funded project then

brought the company, the JIC researchers, and scientists from

Germany, Denmark, Italy and Switzerland together to develop it

further4. The JIC researchers are helping to increase the amount of

the lantibiotic produced by the bacteria. “A big issue for pharma

companies, when they proceed towards clinical trials, is getting

enough of the natural product, because often these compounds

are made in very small amounts,” says Professor Bibb.

“By understanding how the gene cluster is regulated we’ve been

able to manipulate the natural producer and make

significantly more.”

NAI-107 is now on the verge of entering phase I clinical trials

to treat MRSA. The market for MRSA therapeutics was estimated

to be worth around $2.7Bn in 2012, growing to $3.4Bn in 20195.

Fundamental bacterial biologyThe researchers at JIC are interested in the fundamental biology

of actinomycetes – how natural products such as NAI-107 are

made and regulated by the bacteria. However, Professor Bibb is

also keen to ensure his work is of use to industry, and collaborates

with researchers from pharmaceutical companies. “We develop a

lot of technology, and fundamental understanding which we feed

in to pharma and to small biotech companies. Additionally, two

start-up companies have resulted from work carried out in our

group,” he explains.

One of those companies, Novacta Biosystems6, was established in

2003 based on intellectual property developed by JC researchers

studying the lantibiotic cinnamycin, from Streptomyces

cinnamoneus bacteria. The group, in collaboration with Novacta,

Image: Slide culture of Streptomyces sp.

Credit: US Centers for Disease Control and Prevention



developed a method using synthetic biology to construct ‘arti-

ficial’ genes to generate variants of cinnamycin7, based on their

understanding of how the bacteria produce and regulate the

compound8. Novacta adopted this technology to develop and

screen around 170 variants of cinnamycin for their antimicrobial

properties.

The same technology was later used by Novacta during their

in-house programme to develop an antibiotic based on the

lantibiotic actagardine, which can be used to treat Clostridium

difficile infections. A semi-synthetic variant of actagardine called

NVB302 has successfully passed phase I clinical trials and is now

waiting to enter phase II9.

A potent antibioticProfessor Bibb is also using synthetic biology to develop

improved variants of the antibiotic tunicamycin, produced by the

actinomycete Streptomyces chartreusis10. Working with Professor

Ben Davis’ group at Oxford, Professor Bibb and colleagues are

investigating whether it is possible to use synthetic biology to

modify tunicamycin to make it more suitable for use as a human

antimicrobial.

“It’s a very potent antibiotic,” says Professor Bibb. “The attractive

thing from an antimicrobial perspective is that it has a clinically

unexploited target. It targets the production of lipid I, which is

used in the production of the bacterial cell wall. No one else has

used that as a target, so there is no resistance out there in the

clinic at the moment.”

“The bad thing is that it also inhibits [a vital biological process

called] protein glycosylation in people, so it is toxic.”

The aim of the latest project is to use synthetic biology to modify

tunicamycin so that is loses its toxic effects in people while

retaining its antimicrobial properties11.

BBSRC and its predecessors have funded research into the

biology of the actinomycetes, and in particular a species called

Streptomyces coelicolor, since the 1960s12. Much of this research

was conducted at JIC, and in 2002 resulted in the first sequence

of an actinomycete genome; that of S. coelicolor.

References1. 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



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.

Wound dressing provides glowing evidence of infection

Bacteria detecting technology When Professors Stephen Rimmer1, Sheila MacNeil2 and Ian

Douglas3 presented the results of their EPSRC/MoD supported

research into branched polymers to military scientists at Porton

Down, it was clear the next stage would be to develop a fast,

accurate and possibly life-saving technique for detecting the

presence of bacteria in wounds.

Professor Rimmer, who heads an interdisciplinary team of polymer

scientists, microbiologists and tissue engineers at the university,

says: “The polymers we have developed incorporate a fluorescent

dye and are engineered to recognise and attach to bacteria,

collapsing around them as they do so. The level of fluorescence

detected will alert clinicians to the nature and the severity of

infection. We were the first people to propose this theory.”

The team’s work also makes for a much more efficient use of

antibiotics. “When the polymer collapses it traps the bacteria

around it, allowing us to pull the whole thing out without releasing

any antibiotics into the wound. This means the bacteria do not

develop any antibiotic resistance – which is crucial for patients

suffering from chronic wounds who need long-term care,” says

Professor Douglas.

From fundamental science to real applicationHaving published papers describing the research in prestigious

journals, the team were looking for sponsorship to take the

technology closer to real application when Professor MacNeil

was invited to a national science conference and the team’s work

started to gain wider public recognition.

Dr Mark Richardson, Vice President of Research and Technology at

Smith & Nephew Wound Management4, had been following the

team’s work. He says: “We knew the team’s research had been well

funded; that it was innovative, of the highest quality and of global

significance for the treatment of wounds. While we would not

normally get involved at the applied research stage, because

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.



of the EPSRC funding and the possibility of Technology Strategy

Board5 support, we could see the benefits of collaborating with

the Sheffield research team to help develop and build their

technologies into some of our existing products.”

With follow-on funding from the Technology Strategy Board,

a joint University of Sheffield and Smith & Nephew team is now

developing the technology that will provide enhanced care for

patients suffering from chronic wounds such as diabetic foot

ulcers and venous leg ulcers.

Dr Richardson adds: “Chronic wounds such as these are major

health and economic burdens in most developed countries and

are primarily wounds of the elderly. With the rise in the levels of

obesity/diabetes this problem can only get worse. These are

critical wounds. If they become infected they can be very

problematic for the patient, in some cases leading to the

amputation of digits or limbs. The early and accurate detection

of infection is very important, but at the moment we have no

point-of-care diagnosis for wounds. Clinicians can take swabs, but

this can mean a delay of up to 48 hours to get a result, during

which time the patient is potentially at risk.”

Rapid responseThe new wound dressings will look very much like

conventional wound dressings, but will contain a hydrogel

membrane. A handheld device will be able to detect changes in

the colour of the dressing, indicating the presence of bacteria

and how best to treat it.

Providing the clinician and the patient with a tool that alerts them

early to a potential infection – and which also reassures them

when there is no infection – could transform the care of wounds

and reduce the unnecessary use of antibiotics. By highlighting

the presence of an infection at an early stage, it could also help

prevent wounds becoming colonised by an established layer of

bacteria (biofilms) which are more resistant to normal antibiotic

treatment and can lead to protracted care.

In the UK alone there are over 200,000 patients suffering from

chronic foot ulcers, with up to 60 per cent of these being

infected. By finding a way of detecting and treating these cases

earlier, and more effectively, the team are confident their research

will improve patient care and reduce the cost burden on the

National Health Service. The aim is to have the new technology

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.



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.

Bacteria-eating viruses

Bacteriophages were discovered and used as a therapy for

bacterial infections almost 100 years ago, long before the

development of antibiotics. Dr Frederick Twort, a British

bacteriologist and later recipient of MRC funding, is credited with

their initial discovery in 1915. French-Canadian scientist Felix

d’Herelle later developed them to treat infections following his

independent discovery of them in 1917.

To date however, they are not in widespread use. Although phages

did reach commercial production in the 1940s, and have been

used to treat several bacterial infections, treatment does not

produce consistent results. In the pre-antibiotic area, many

aspects of phage biology were not well understood. Doses of

phages often did not contain enough viable viruses to be

effective, and viruses were used that did not kill the intended

bacteria1. There were also problems with the production of a

stable contaminant-free phage stock. Perhaps the greatest barrier

to phage acceptance in the west was the inadequate scientific

methods used by researchers, such as the exclusion of placebos

in trials2. With the advent of the antibiotic dawn, phage research

and production were all but shelved, with the exception of Eastern

Europe and the former Soviet Union where they continue to be

used therapeutically.

Renewed interestNow the threat of widespread antimicrobial resistance has sparked

a renewed interest in phages. Dr Clokie has been studying phages

for 14 years. She says, “As their natural enemy, phages

specifically target and kill bacteria. They encode a diverse set of

gene products that can potentially be exploited as novel

antimicrobials. They have the advantage over antibiotics of being

much more specific and, as they can self-replicate at the site of

an infection, they are able to clear infections that antibiotics can’t

reach.” Over the past few years, Dr Clokie has isolated and

characterised 40 different phages that infect C. difficile — the

largest known set of these phages. Of these, she has developed

a specific mixture that has proved to be effective against 90 per

cent of the most clinically relevant C. difficile strains seen in the

UK. The US pharmaceutical company AmpliPhi are funding the

further development of these phages, with the aim of testing

them in Phase I and Phase II trials. This will involve optimising

phage preparations for maximum effectiveness against C. difficile

infections and establishing production, storage and delivery

systems for the phage mixture. Dr Clokie will evaluate the

effectiveness of the therapy and dosing regimes in collaboration

with Dr Gill Douce at the University of Glasgow.

Image: Bacteriophage.

Credit: BlueSci. Cambridge University science magazine.



Dr Clokie says, “The number of bacteriophages that exist on Earth,

combined with their vast genetic diversity and exquisitely specific

interactions with bacterial hosts means that they have the

potential to offer a real solution for the treatment of a range of

human pathogens. A lot of fundamental science needs to

be carried out in order to ensure that we understand how to best

exploit them.”

Phage productsA 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

identify small molecules that mimic the structure and function of

Gp2 and use these as the basis for new drugs to combat

bacterial infections.

Different bacterial infections will require different treatment

solutions, but it is hopeful that both whole phage particles and

their products can be developed as important alternative

treatments for human infection.

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



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.

Making the leap: Cross-species transmission of Staphylococcus aureus

Research led by Professor Ross Fitzgerald1 from the Roslin Institute

at the University of Edinburgh, and others, has found that

S. aureus has made numerous leaps between host species; from

humans to animals such as dairy cattle and pigs and vice versa.

In particular, a 2013 study by Professor Fitzgerald and colleagues

showed that a bovine strain called CC97 had made two separate

leaps to humans2. “There may be a lot more cross-species

transmission than we anticipated,” says Professor Fitzgerald.

Following these transmissions, CC97 spread to people on four

continents over a forty year period. During that time, the strain

also acquired resistance to common antibiotics, becoming

methicillin-resistant S. aureus, or MRSA.

The findings suggest that farm animals can provide a ‘reservoir’

of S. aureus and MRSA strains that can spread to and cause

disease in human populations.

The emergence of resistanceAntibiotic use is widespread in animal farming, including the

dairy industry and pig farming, as well as in human medicine, so

researchers might have expected to see resistance evolving in

strains of S. aureus present in dairy cattle, as it does in people.

However, Professor Fitzgerald found that strains of CC97 S. aureus

in cattle were not resistant to the antibiotic methicillin. Only once

CC97 strains had crossed to humans and pigs did they acquire

resistance to methicillin, and further work is needed to

understand why resistance arose in some strains of the bacteria

but not others.

“There may be something about the pig farming industry that

lends itself to the emergence of antibiotic-resistant strains of

S. aureus,” speculates Professor Fitzgerald. “We’ve seen that for

several different strains [from pigs] now – they acquire methicillin

resistance. We don’t see that to the same level in dairy cows.”

A widespread pathogenS. aureus is a widespread pathogen of humans and of livestock.

In 2013-14, the NHS reported 826 cases of MRSA infection, and

9,290 cases of infection by S. aureus susceptible to the antibiotic

methicillin3. S. aureus is also the leading cause of bovine mastitis,

a painful inflammation of the mammary tissue, which costs the

UK dairy industry £200M a year4. The bacteria also cause mastitis

in sheep and goats, and various conditions in broiler chickens,

including septic arthritis.

As a result, the livestock industry relies on antibiotics to

prevent and treat the infection, which can result in the emergence

of antimicrobial resistance. Globally, around 70 per cent of

antimicrobial use is in farm animals5.

Image: Cows on Eefie Hill.

Credit: John Comloquoy CC BY-SA 2.0, http://creativecommons.org/

licenses/by-sa/2.0/deed.en

http://creativecommons.org/licenses/by-sa/2.0/deed.en

http://creativecommons.org/licenses/by-sa/2.0/deed.en



Almost nine hundred strainsPrevious studies by Professor Fitzgerald and others found that

different strains of S. aureus are associated with different

host species, and have become adapted to the conditions those

hosts provide. The researchers wanted to understand where the

ancestor of these strains came from, and when and how S. aureus

made the leap between host species.

To do so, they previously used a technique called ‘multi-locus

sequence typing’ to identify genetic changes that had occurred in

the strain at certain locations, or loci, within their genomes.

This could tell the researchers which strains were closely-related

and enabled them to estimate when two strains shared a

common ancestor. Genetic changes accrue over time, so strains

that have been separated for a long time have more genetic

differences than strains that have only recently evolved from a

common ancestor.

The subsequent development of whole-genome sequencing gave

researchers a powerful tool to look for genetic changes in the

entire genome of S. aureus strains. Professor Fitzgerald is now

involved in a collaborative project using whole genome sequences

of almost 900 S. aureus strains. The researchers will study how

the bacteria have jumped between hosts across an entire species,

rather than focussing on a single S. aureus strain such as CC97.

They also plan to look at the acquisition of antibiotic resistance

across all of these strains, and whether it is more likely to appear

in certain hosts.

References1. 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



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.

Whole genome sequencing

Infectious diseases are often transmitted globally. So rapid

detection and identification of outbreaks, and the exchange of

information between different authorities and research facilities,

are essential to identify trends and control spread2. WGS could

have a major part to play in this process.

Impact on patient careProfessor Sharon Peacock at the University of Cambridge

specialises in the role of sequencing technologies in diagnostic

microbiology and public health. In 2013 she provided the first

evidence that bacterial WGS could be used in clinical practice to

impact on patient care3. The infection control team at the study

hospital had identified several infants in a special care baby unit

(SCBU) infected with superbug methicillin-resistant

Staphylococcus aureus (MRSA) over a six-month period. Although

a link was suspected, a persistent outbreak could not be confirmed

with conventional methods. The use of WGS confirmed the

outbreak, and also identified a larger population of 26 related

cases. Analysis showed that transmission had occurred within the

SCBU, between mothers on a post-natal ward, and in the

community. WGS data were used to propose and confirm that

infection by a staff member had enabled the infection to persist

during periods without known infection on the SCBU and after

a deep clean. This individual was successfully treated, after which

the outbreak ceased. This demonstrated that healthcare and

community-associated infection should no longer be regarded as

separate entities.

Professor Peacock says, “This study demonstrates that

sequencing of microbial pathogens can influence the quality of

infection control and patient care.”

Better antimicrobial stewardshipMRC-funded researchers at the University of Oxford have also

used WGS to assess the transmission of fellow superbug

Clostridium difficile (C.difficile)4. Dr David Eyre and Professor Sarah

Walker demonstrated that far fewer cases of C. difficile infection

were transmitted from symptomatic patients than expected, with

other cases mostly likely coming from asymptomatic individuals or

an environmental source such as water or animals, and food. They

analysed whole genome sequences of samples obtained from all

patients with C. difficile infection in Oxfordshire over 3.6 years and

found that 45 per cent were sufficiently genetically diverse to

suggest transmission from sources other than symptomatic

patients. However, the whole genome sequences were also used

to show that the incidence of cases transmitted from other

symptomatic patients and cases from other sources both

declined similarly over the study. These results demonstrate the

importance of interventions to reduce susceptibility to disease in

Image: Automated DNA sequencing output of human chromosome 1.

Credit: Wellcome Images/The Sanger Institute



exposed patients, such as better antimicrobial stewardship, rather

than just reducing transmission from symptomatic patients. They

also illustrate the value in combining information from whole

genome sequencing with traditional epidemiology. The use of

rapid benchtop sequencing5 again allowed the identification of

genetically related cases in almost real time so that cases clearly

linked by a hospital or community contact can be targeted to

prevent further spread.

100,000 genomes projectOther MRC-funded researchers in Oxford have also

demonstrated the value of using whole genome sequencing to

investigate clusters of cases of Mycobacterium tuberculosis6,7.

Professors Derrick Crook and Tim Peto found that whole genome

sequencing could identify previously unrecognised links between

cases, more than doubling the number of tuberculosis

transmissions previously identified through standard methods.

It was also able to refute the possibility of transmission between

other cases, saving hours of work trying to work out how

transmission could have happened. The technique could also

identify super-spreaders and predict the existence of undiagnosed

cases, potentially leading to early treatment of infectious patients

and their contacts. This work has led to whole genome

sequencing being adopted by Public Health England, initially in a

pilot study within the “100,000 genomes” project, working

towards widespread implementation in English tuberculosis

reference laboratories from 2016.

Professor Peacock has also successfully used WGS to investigate

a case of multi drug-resistant (XDR) Mycobacterium tuberculosis8.

This proved more accurate than standard methods, with WGS

detecting mixed infection by two distinct strains of

M.tuberculosis, which was not identified by standard genotyping.

This has important implications for distinguishing relapse from

reinfection and for identifying secondary cases of infection. The

study also highlighted the potential of WGS to predict the

antimicrobial resistance of M.tuberculosis, which could reduce the

time taken to implement effective antimicrobial therapy for XDR

M.tuberculosis. This would benefit individual patient care and

could help to contain the spread of infection.

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

by Alexander Fleming.

Fleming, A. (1929) On the antibacterial action of cultures of a

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

subject of the first ever

randomised medical trial,

run by the MRC.

‘Aminoglycoside’. (2014). Encyclopædia Britannica Online.

Retrieved 11 September, 2014, from http://www.britannica.com/

EBchecked/topic/20760/aminoglycoside

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



Cephalosporins Cefalexin 1945 Around 1956 Resistance to

cephalosporins was already

present in nature when the

antibiotics were developed.

This date is based on when

researchers identified the

specific enzymes that could

break down cephalosporin.

Turek, M. (1982) Cephalosporins and related antibiotics: an

overview. Review of Infectious Diseases. 4 (supplement).

http://cid.oxfordjournals.org/content/4/Supplement_2/S281.full.

pdf

Abraham, E.P. &, Newton, G.G.

1956. A comparison of the action of penicillinase on

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




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

‘second generation’

quinolones introduced in

1978. The quinolones were

first introduced in 1962, and

resistance appeared in 1968.

Crook, S.M., Selkon, J.B. & Mclardy Smith, P.D. (1985) Clinical

resistance to long-term oral Ciprofloxacin. The Lancet.

325 (8440), 1275, doi:10.1016/S0140-6736(85)92343-8

http://www.thelancet.com/journals/lancet/article/PIIS0140-

6736(85)92343-8/fulltext

Glycopeptides Vancomycin 1953 1986 Vancomycin is the current

antibiotic of last resort for

tackling MRSA infections.

However, vancomycin

resistant S. aureus, or VRSA,

first appeared in 2002.

Levine, D.P. (2006) Vancomycin: A History. Clinical Infectious

Diseases. 42:S5–12 Available online: http://cid.oxfordjournals.org/

content/42/Supplement_1/S5.full.pdf


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.

Documents

Antimicrobial Resistance Timeline Report - MRC