Antimicrobial Resistance Timeline Report - MRC
Transcript of 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.
Antimicrobial resistance
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/
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
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.
© Medical Research Council 2014
Antimicrobial resistance
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
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Antimicrobial resistance
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’.
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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.
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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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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.
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3. http://www.bbsrc.ac.uk/publications/impact/david-phillips-fellowships.aspx
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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.
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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).
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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.
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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
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Antimicrobial resistance
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.
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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/
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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.
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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
© Medical Research Council 2014
Antimicrobial resistance
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.
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
Antibiotic class1 Example Class discovered Resistance identified2 Notes Reference
© Medical Research Council 2014
Antimicrobial resistance
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
Antibiotic class1 Example Class discovered Resistance identified2 Notes Reference
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.