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.
Organisations
- University of Warwick, United Kingdom (Lead Research Organisation)
- University of Oxford, United Kingdom (Collaboration)
- Defence Science & Technology Laboratory (DSTL) (Collaboration)
- AstraZeneca plc (Collaboration)
- Novartis (Collaboration)
- Novacta Biosystems Ltd (Collaboration)
- MRC-Technology (Collaboration)
- Cubist Pharmaceuticals (Collaboration)
- Vita-Salute San Raffaele University (Collaboration)
- Basilea Pharmaceutica (Collaboration)
Publications

Aggarwal SD
(2021)
A molecular link between cell wall biosynthesis, translation fidelity, and stringent response in Streptococcus pneumoniae.
in Proceedings of the National Academy of Sciences of the United States of America

Batson S
(2017)
Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine.
in Nature communications

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

Bojer MS
(2019)
SosA inhibits cell division in Staphylococcus aureus in response to DNA damage.
in Molecular microbiology

Briggs NS
(2021)
The Pneumococcal Divisome: Dynamic Control of Streptococcus pneumoniae Cell Division.
in Frontiers in microbiology

Bugg TD
(2016)
Inhibition of phospho-MurNAc-pentapeptide translocase (MraY) by nucleoside natural product antibiotics, bacteriophage ?X174 lysis protein E, and cationic antibacterial peptides.
in Bioorganic & medicinal chemistry

Catherwood AC
(2020)
Substrate and Stereochemical Control of Peptidoglycan Cross-Linking by Transpeptidation by Escherichia coli PBP1B.
in Journal of the American Chemical Society


Lloyd AJ
(2013)
Adenosine tetraphosphoadenosine drives a continuous ATP-release assay for aminoacyl-tRNA synthetases and other adenylate-forming enzymes.
in ACS chemical biology

Lund VA
(2018)
Molecular coordination of Staphylococcus aureus cell division.
in eLife
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 | Chair of Scientific Committee Antibiotic Research Uk |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Impact | Patient focussed dialogue regarding antibiotic effectiveness and patient informed research |
URL | https://www.antibioticresearch.org.uk |
Description | Civil Society Discussion on IACG Recommendations on Global Governance of AMR". |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a advisory committee |
Impact | Civil Society Discussions relating to Future Global Governance for Antimicrobial Resistance discussion paper publish July 2018 |
URL | https://www.who.int/antimicrobial-resistance/interagency-coordination-group/IACG_Future_global_gover... |
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 | UN General Assembly |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a national consultation |
Impact | Invited to attend Wellcome Trust Organised Event at UN GA New York 2016 |
URL | https://digitallibrary.un.org/record/842813?ln=en |
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 | Public |
Country | United Kingdom |
Start | 05/2016 |
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 | 08/2013 |
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 | Public |
Country | United Kingdom |
Start | 08/2015 |
End | 03/2021 |
Description | Medical and Life Sciences Research Fund |
Amount | £40,000 (GBP) |
Organisation | Medical and Life Sciences Research Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2013 |
End | 01/2014 |
Description | The Physics of Antimicrobial Resistance |
Amount | £2,158,027 (GBP) |
Funding ID | EP/T002778/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2022 |
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 | 05/2016 |
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 | Improved technique to label bacterial cell walls |
Description | We improved the in sito labelling technique for bacterial cell wall with fluorescent D-amino acids. |
Type Of Material | Technology assay or reagent |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | The improved research tool is now available for the scientific community. |
URL | https://bio-protocol.org/e3316 |
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 | Academic/University |
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 | Soap box science 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Public presentation of scientific topics at the Monument city centre of Newcastle upon Tyne, called soap box science, by women. Daniela Vollmer (Research Technician in the group) participated in this event. |
Year(s) Of Engagement Activity | 2018 |
URL | http://soapboxscience.org/ |
Description | UK CHINA: CHNUK virtual workshops and research seminar series |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation/ discussion with Brazilian microbiology groups as to how develop and work effectively as national and international consortia in AMR discovery |
Year(s) Of Engagement Activity | 2020 |
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 |