Team CanUK: Novel antibacterial targets, assays, probes and opportunities in bacterial cell wall biogenesis

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

Millions of people die each year from bacterial infections and tens of millions suffer from the consequences of these infections. The discovery of the antibiotic penicillin once opened the door to treat these infections by stopping bacteria making the polymer in the cell wall that holds them together. This polymer, called peptidoglycan, is made up of an interlocking network of sugars and strings of amino acids (peptides). Specialised proteins (called PBPs), with the ability to stitch together these sugars and peptides are the targets inhibited by penicillin, stopping cell wall synthesis and killing the bacterium. Many important bacteria are no longer killed by penicillin and other antibiotics that attack other stages in the production of peptidoglycan. Bacteria have changed, evading the action of these antibiotics. We need to fight back. Our progress until recently has been hampered by our inability to routinely synthesise the key chemical components that make this polymer. We can now do this. This is exciting, as we develop the capability to explore important unanswered questions about how bacteria grow and control the production of peptidoglycan. We wish to pull together the expertise of UK and Canadian scientists in a cooperative and coordinated partnership to increase our understanding of the fundamental biology of this process. All of this will open fundamentally new biological insights, and opportunities to use these for the future development of new antibiotics that will work against multiply antibiotic resistant bacteria like MRSA and TB.

Technical Summary

There is a currently a global health threat posed by emerging antibiotic resistance amongst clinically important bacteria which is compounded by the decline in new drugs coming to the market. The bacterial cell wall (peptidoglycan, PG) is a validated, important, target for existing antibiotics and is a fundamental biological process, which is still poorly understood. Previous MRC funding in the UK has been used to create a research network focussed on PG with a synthesis facility at Warwick. This facility provides bespoke PG reagents to the research community that are not available commercially and has been a significant breakthrough in our capacity to address unanswered questions within the pathway. Researchers in Canada also have a track record of research in this area along with facilities for high throughput screening and compound libraries that can take advantage of new assays and substrates. The purpose of this UK-Canada network is thus to facilitate the development of bilateral research programmes with the aim of unravelling key features of bacterial cell wall biosynthesis using an integrated approach in which cell wall are analysed in a hierarchical manner from the fundamental biochemistry of peptidoglycan biochemistry, through sub-cellular organisation of the assembly machinery, to cell polymerisation. The aims are to understand the interrelationships between the formation of precursors, their export, polymerisation, modification and recycling to inform our fundamental understanding of the system. Overarching this is a desire to use this information in a rational manner to ultimately develop novel antimicrobials and identify new antimicrobial targets.

Publications

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Bern M (2017) Towards an automated analysis of bacterial peptidoglycan structure. in Analytical and bioanalytical chemistry

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Majce V (2013) Crystallization and preliminary X-ray analysis of a UDP-MurNAc-tripeptide D-alanyl-D-alanine-adding enzyme (PaMurF) from Pseudomonas aeruginosa. in Acta crystallographica. Section F, Structural biology and crystallization communications

 
Description All Party Parliamentary Group on Antimicrobial Resistance
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Attendance at All Parliamentary Group for AMR
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Help shaped national AMR policy
 
Description Canada/UK AMR Workshop
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
 
Description Lessons to be learnt from pharma A summary of an interactive one-day symposium about discovery and development of new antibacterial drugs 1 Lessons to be learnt from pharma about discovery and development of new antibacterial drugs
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description MRC strategic review on antimicrobial resistance
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Accelerate CHNUK AMR discovery: Establishing joint China/UK training and research platforms enabling highthroughput fragment based inhibitor discovery
Amount £1,000,000 (GBP)
Funding ID MR/P007503/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description BBSRC LINK award
Amount £464,000 (GBP)
Funding ID BB/K017268/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 09/2015
 
Description Coventry General Charities
Amount £40,000 (GBP)
Organisation General Charity of the City of Coventry 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 01/2015
 
Description MRC AMR theme 1 collaboration award
Amount £3,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2015 
End 09/2020
 
Description Medical and Life Sciences Research Fund
Amount £40,000 (GBP)
Organisation Medical and Life Sciences Research Fund 
Sector Charity/Non Profit
Country Unknown
Start 01/2013 
End 01/2014
 
Description Wellcome Trust Innovation Award
Amount £100,000 (GBP)
Funding ID 109676/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 06/2017
 
Description flexible interchange partnership FLIP
Amount £150,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2014 
End 02/2016
 
Title New assays for penicillin binding proteins 
Description First in class continuous quantitative bifunctional PBP assay 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Use in HTS assay with Astra Zeneca 
 
Title peptidoglycan pathway intermediates 
Description Capacity to synthesise peptidoglycan intermediates at high purity and semi-commercial quantities 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Access of reagents to the wider community - supplied over 40 research groups worldwide 
 
Title tRNA synthetase assay 
Description new continuous assay for drug discovery 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact new tools for pharma 
 
Description Astra Zeneca global screening platform 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Knowledge transfer, biological insight and assay development
Collaborator Contribution Advice, knowledge transfer, training and access to high throughput screening platforms and chemical libraries
Impact Novel assay development and assay validation Hit screening underway
Start Year 2013
 
Description CAN UK Industry partner 
Organisation AstraZeneca
Department Infection
Country United Kingdom 
Sector Private 
PI Contribution Supply of reagents and advice around assay design and development
Collaborator Contribution Research funds, in kind support (£290000 from AZ), and advice plus support for future pending grant applications
Impact Successful BBSRC LINK grant with Astra Zeneca - total value £1.1M
Start Year 2011
 
Description CAN UK Industry partner 
Organisation Basilea Pharmaceutica
Country Switzerland 
Sector Private 
PI Contribution Supply of reagents and advice around assay design and development
Collaborator Contribution Research funds, in kind support (£290000 from AZ), and advice plus support for future pending grant applications
Impact Successful BBSRC LINK grant with Astra Zeneca - total value £1.1M
Start Year 2011
 
Description CAN UK Industry partner 
Organisation Cubist Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Supply of reagents and advice around assay design and development
Collaborator Contribution Research funds, in kind support (£290000 from AZ), and advice plus support for future pending grant applications
Impact Successful BBSRC LINK grant with Astra Zeneca - total value £1.1M
Start Year 2011
 
Description CAN UK Industry partner 
Organisation Novartis
Department Infectious Diseases
Country United States 
Sector Private 
PI Contribution Supply of reagents and advice around assay design and development
Collaborator Contribution Research funds, in kind support (£290000 from AZ), and advice plus support for future pending grant applications
Impact Successful BBSRC LINK grant with Astra Zeneca - total value £1.1M
Start Year 2011
 
Description Developing new reagents to underpin pharmaceutic research 
Organisation Vita-Salute San Raffaele University
Country Italy 
Sector Academic/University 
PI Contribution Provision of reagents as biological standards to help inform assay development
Collaborator Contribution Discussion and insight into screening strategies and fundamental science underpinning antibiotic discovery
Impact knowledge transfer
Start Year 2014
 
Description Exploring peptidoglycan polymerization 
Organisation Cubist Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Provision of commercially unavailable reagents and knowhow to assist in assay development
Collaborator Contribution iterative feedback on assay development and outcome
Impact Have obtained letters of support from Cubist for recent grant applications and developed a good working relationship with their senior scientists
Start Year 2013
 
Description MRCT 
Organisation MRC-Technology
Department MRCT Centre for Therapeutics Discovery (CTD)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Provision of reagents and assays, developing structural information
Collaborator Contribution Pump priming drug discovery research and further grant applications to MRC
Impact DPFS grant applications
Start Year 2008
 
Description New assays and reagents to exploit peptidoglycan biosynthesis 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Development of new reagents and assays
Collaborator Contribution Insight into establishment of high throughput screening approaches, pitfalls and access to equipment
Impact Wider collaboration with other global pharma, new grant applications, increased industrial understanding, training and skills for researchers and students
Start Year 2013
 
Description Novacta 
Organisation Novacta Biosystems Ltd
Country United Kingdom 
Sector Private 
PI Contribution updating company on our assay development and screening capabilities
Collaborator Contribution Indistrial focussed advice
Impact Novacta became industrial advisors as part of our MRC programme grant application and Mike Dawson from Novacta still performs this function
 
Description Peptidoglycan flux and inhibition 
Organisation Basilea Pharmaceutica
Country Switzerland 
Sector Private 
PI Contribution Developing new insight into the ealy stages of peptidoglycan biosynthesis and how protein protein interaction may impact upon ability to inhibit these reactions
Collaborator Contribution Historical insight and approaches to targeting these enzymes
Impact Knowledge transfer
Start Year 2012
 
Description Underpinning technology to exploit peptidoglycan biosynthesis 
Organisation Defence Science & Technology Laboratory (DSTL)
Country United Kingdom 
Sector Public 
PI Contribution Insight into the assembly of the cytoplasmic phase of peptidoglycan biosynthesis
Collaborator Contribution Insight into defence requirements and work leading up to the project
Impact too early - completing initial contracting process
Start Year 2014
 
Description Warwick Oxford Chemistry Collaboration 
Organisation University of Oxford
Department Department of Paediatrics
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing underpinning assays to help inform antibiotic development approaches.....................................
Collaborator Contribution Chemistry input and design
Impact Multidisciplinary
Start Year 2014
 
Title Synthesis of peptidoglycan intermediates 
Description Optimisation of peptidoglycan pathway intermediates synthesis and purification 
IP Reference  
Protection Protection not required
Year Protection Granted 2006
Licensed No
Impact Development of a synthesis facility to provide thes eintemediates to the global research community and the fundamental platform for several UK and international peptidoglycan networks
 
Company Name Antimicrobial Discovery Solutions Ltd 
Description Reagents, assay development and services 
Year Established 2015 
Impact N/A
 
Description ANTRUK Antibiotic Research UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Establishment of new charity and new fundraising campaign

regional and national media interest
Year(s) Of Engagement Activity 2014
URL http://www.antibioticresearch.org.uk
 
Description Getting to grips with antibiotic resistance 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact The School of Life Sciences at Warwick hosted members of the public and press for a presentational evening with talks, lab tours and demonstrations in an event entitled: "Getting to grips with antibiotic resistance" This event was held in antibiotic awareness week in November 2016 and hosted around 90 visitor
Year(s) Of Engagement Activity 2016
URL http://www2.warwick.ac.uk/fac/sci/lifesci/outreach/next/
 
Description MRC Flemming video 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact 100000. Short film presentation linking our current MRC funded research to the groundbreaking work by alexander Flemming

to be released later this year as part of the MRC celebrations
Year(s) Of Engagement Activity 2013
 
Description O'Neil AMR review 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact In December we published our first report1
showing that infections caused by
drug-resistant pathogens are one of the biggest health problems the world faces
today. Bacteria and other pathogens have always evolved to resist the new drugs
that modern medicine uses to combat them. But in recent years the rise in drug
resistance has been a particular worry, especially the emergence of antibioticresistant
superbugs. Unless action is taken to address this huge global issue, our
conservative estimate is that it will cost the world an additional 10 million lives
a year by 2050, more than the number of people currently dying from cancer
annually. It will also have a cumulative cost of 100 trillion USD, more than one
and a half times annual world GDP today, or roughly the equivalent to losing the
UK economy from global output every year.
We now turn our attention to how this problem can be tackled. This paper is the
first in a series that works towards global and sustainable solutions. There are
many angles to the problem that we will need more time to consider. In particular,
the focus of our next paper, due to be published in the spring, will be how to
stimulate the market for companies to invest in and develop new antimicrobials and
diagnostics, which is not fully addressed here. There we will assess potential 'push'
and 'pull' incentives to encourage the development of new antimicrobial drugs,
and set out our proposals for action by policy makers. In later papers we will also
focus on important issues such as the use of antibiotics in agriculture and potential
alternatives to antimicrobials
Year(s) Of Engagement Activity 2015
URL https://amr-review.org/sites/default/files/Report-52.15.pdf
 
Description Pew Road Map for Antibiotic Discovery 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The Pew Charitable Trusts convened a multidisciplinary group of leading industry and academic experts to
identify the key scientific roadblocks to antibiotic discovery and consulted with numerous other public and
private sector stakeholders to develop a Scientific Roadmap for Antibiotic Discovery. The roadmap outlines a
concrete approach-both a scientific plan and organizational structure to support this research-that would lay a
foundation for the sustained and diversified discovery and development of new antibiotics and therapies over the
coming decades.The report's key findings show a need for:
• A targeted approach to tackle the basic scientific barriers impeding antibiotic discovery and development.
• A better understanding of how to overcome the cellular defenses of drug-resistant Gram-negative bacteria,
which cause some of the most difficult-to-treat infections.
• Generation of new chemical matter designed for antibiotic discovery.
• Tools and methodologies to evaluate promising alternatives to traditional antibiotic use.
• A framework for sharing information, expertise, and materials across the research community to foster
innovative science and spur the discovery of novel antibacterial therapies.
Year(s) Of Engagement Activity 2016
URL http://www.pewtrusts.org/~/media/assets/2016/05/ascientificroadmapforantibioticdiscovery.pdf
 
Description Regional news papers 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Contribution to regional news

Further contacts from regional and national media
Year(s) Of Engagement Activity 2006,2007
 
Description Shambala Festival August 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Krebsfest went on tour to the Shambala Festival with series of talks and workshops.
Year(s) Of Engagement Activity 2016
 
Description Virtual reality E. coli 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We developed a virtual reality E. coli experience that was used at Festival of the Mind in September 2016. Hugely successful.
Year(s) Of Engagement Activity 2016
 
Description Warwick University iCAST 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Communication to UK and global audience

Further media contacts
Year(s) Of Engagement Activity 2008