MICA: Mechanistic understanding of cell wall biosynthesis to combat antimicrobial resistance
Lead Research Organisation:
University of Warwick
Department Name: School of Life Sciences
Abstract
The discovery of the antibiotic penicillin opened the door to the treatment of a wide range of infections. It works by stopping bacteria from making the polymer in the cell wall (peptidoglycan, PG) that holds them together. This is assembled by specialised proteins (called penicillin-binding-proteins or PBPs, which are present in all bacteria) that either have the ability to stitch together both the sugar backbone and the peptides (these are known as bi-functional enzymes), or either just the sugar back bone or just the peptide-crosslinks (mono-functional enzymes). We know little about how the polymerization and cross linking activities are controlled or co-ordinated, or how they truly interact with their natural substrates. Furthermore, the construction of peptide cross-links by PBPs is famously the target inhibited by penicillin which stops cell wall construction and kills the bacterium.
Penicillin has been an excellent antibiotic, not least because it targets multiple PBPs simultaneously within a bacterium and resistance rarely develops by altering the PBP target (with the notable exception of bacteria that can acquire altered PBP genes from other species that are poor targets for the antibiotic). Unfortunately, many bacteria have acquired resistance to penicillin by other mechanisms. Primarily this has been due to the acquisition of enzymes that degrade the antibiotic (beta-lactamases), or reduce penetration (influx) of antibiotic into the bacterium or increasing the rate of efflux out of the bacterium. We urgently need to fight back and the strategy of exploring PBPs to make better versions of current antibiotics that are more active, can evade beta-lactamases or resistance due to changing influx or efflux. Global pharmaceutical companies have a real interest in progressing such developments, however, they need better mechanistic insight into how PBPs work. We attend to address these fundamental gaps in our understanding.
Why can we succeed where others have failed?
1. Progress in achieving this mechanistic insight has been hampered by past inability to routinely synthesise the key chemical components or precursors that make this polymer. From past MRC and BBSRC funding we can now make key chemical components at Warwick, and have developed an exceptional track record of providing reagents to study peptidoglycan biosynthesis to academia worldwide.
2. Having studied how to synthesise all of the chemical precursors used by different PBPs we have developed completely new continuous assays that will now help us to understand how PBPs polymerise precursors or how they crosslink these. We have one assay to finalise, which would bring together our ability to study polymerization and crosslinking in one reaction. Alongside a continuous crosslinking assay, these new technologies represent a 70 year long breakthrough and world first.
3. Super high resolution imaging is now available so that we can see how PBPs work inside bacteria and in the test tube, how they interact with each other and other proteins or lipids within bacterial cells. We can also study PBP structure at ultra-high resolution to understand how PBPs interact at the molecular level with their natural substrates and different well known antibiotics. We also have access to new chemical approaches, which along with our assays and structural biology will help direct us to new ways to stop these enzymes.
4. Finally, we have brought together international academic experts from across the UK with skills in microbiology, chemistry and physics to work in synchrony and closely with many industry experts and a wider scientific advisory panel. This concentration of effort across a wide skill base with new technology will help ensure rapid progress and results with broad application that will be valuable for future programs of antibiotic discovery and development.
Penicillin has been an excellent antibiotic, not least because it targets multiple PBPs simultaneously within a bacterium and resistance rarely develops by altering the PBP target (with the notable exception of bacteria that can acquire altered PBP genes from other species that are poor targets for the antibiotic). Unfortunately, many bacteria have acquired resistance to penicillin by other mechanisms. Primarily this has been due to the acquisition of enzymes that degrade the antibiotic (beta-lactamases), or reduce penetration (influx) of antibiotic into the bacterium or increasing the rate of efflux out of the bacterium. We urgently need to fight back and the strategy of exploring PBPs to make better versions of current antibiotics that are more active, can evade beta-lactamases or resistance due to changing influx or efflux. Global pharmaceutical companies have a real interest in progressing such developments, however, they need better mechanistic insight into how PBPs work. We attend to address these fundamental gaps in our understanding.
Why can we succeed where others have failed?
1. Progress in achieving this mechanistic insight has been hampered by past inability to routinely synthesise the key chemical components or precursors that make this polymer. From past MRC and BBSRC funding we can now make key chemical components at Warwick, and have developed an exceptional track record of providing reagents to study peptidoglycan biosynthesis to academia worldwide.
2. Having studied how to synthesise all of the chemical precursors used by different PBPs we have developed completely new continuous assays that will now help us to understand how PBPs polymerise precursors or how they crosslink these. We have one assay to finalise, which would bring together our ability to study polymerization and crosslinking in one reaction. Alongside a continuous crosslinking assay, these new technologies represent a 70 year long breakthrough and world first.
3. Super high resolution imaging is now available so that we can see how PBPs work inside bacteria and in the test tube, how they interact with each other and other proteins or lipids within bacterial cells. We can also study PBP structure at ultra-high resolution to understand how PBPs interact at the molecular level with their natural substrates and different well known antibiotics. We also have access to new chemical approaches, which along with our assays and structural biology will help direct us to new ways to stop these enzymes.
4. Finally, we have brought together international academic experts from across the UK with skills in microbiology, chemistry and physics to work in synchrony and closely with many industry experts and a wider scientific advisory panel. This concentration of effort across a wide skill base with new technology will help ensure rapid progress and results with broad application that will be valuable for future programs of antibiotic discovery and development.
Technical Summary
Penicillin and the wider family of beta-lactams are the single most important family of antibiotics. They target the final stage of bacterial cell wall biosynthesis, specifically cross-linking the structural polymer peptidoglycan (PG) by a family of enzymes called penicillin-binding-proteins (PBPs). Given this pivotal importance of PBPs we know little about how they interact with their natural substrates, precisely what these substrates are for different PBPs, and, astonishingly, how beta-lactam antibiotics interfere with this process. The SWaN Alliance brings together a multidisciplinary team of the UK's leading experts in PG biology, imaging and PG focussed chemistry to tackle these outstanding questions. Our aim is to build an integrated, multi-centre, multidisciplinary research programme as the UK hub of activity in cell wall biosynthesis. This hub will, in the first instance, develop new insight, and open up new ways to target PBPs, to sidestep the current mechanisms of resistance. We intend to decipher the fundamental mechanisms of PBPs at the structural, functional and cytoplasmic levels, including how PBPs interact with their substrates, and how the two PBP enzymatic (transpeptidase and transglycosylase) activities are co-ordinated. This will include, for the first time, determination of kinetic constants for the TP reaction of PBPs and the development of a dual quantitative continuous TP/TG assay. We will extend this new functional and structural insight, to explore interactions of PBPs with landmark beta-lactams, recently developed novel non-lactam PBP inhibitors, and control proteins. In doing so we will develop a transformative understanding of how PBPs interact with beta-lactams from which we will better understand the role of PBP alterations and substrate alterations in the emergence of target mediated resistance. All of this activity will reinvigorate PBPs as targets for drug discovery and development by industry and academia.
Planned Impact
Antibiotics have been a mainstay of human healthcare for over 70 years. However, the inexorable spread of antibiotic resistance limits their ability to prevent and to cure life-threatening diseases. One of the most important and enduring targets for antibiotics is the biosynthesis of the bacterial cell wall. The predominant structural component of the wall is peptidoglycan, the synthesis of which is the target of penicillin and other clinically-relevant antibiotics such as methicillin, cephalosporins and carbapenems. Peptidoglycan is polymerized and cross-linked by a family of enzymes called penicillin-binding-proteins (PBPs) that are the single most important family of antibiotic targets known. Given the pivotal importance of PBPs in human healthcare, it is astounding that we still understand little of how peptidoglycan is made, how this process is controlled and how antibiotics interfere with it at the biochemical, structural and cellular levels. This information is vitally important to (1) help inform global pharma with current lactam projects with new mechanistic and structural insight for further development and (2) underpin the search for non-lactam antibiotics that target PBPs, with the bold objective of side-stepping decades of beta-lactamase evolution in one leap.
This proposal brings together a globally unique group of recognised world leaders in complementary aspects of bacterial biochemistry, chemistry, genetics, physics and physiology in the area of peptidoglycan metabolism, structure and architecture. Our aim is to build from this proposal a nationally integrated, multi-centre, multidisciplinary programme of research to address the critical and unresolved understanding of PBPs in relevant Gram negative and Gram positive pathogens that is essential for future antibiotic discovery.
This will extend key competencies and capabilities of academia to support and engage effectively with the global biotechnology and pharmaceutical sector. As such the project will have diverse impacts within the UK and internationally. Some of the expected impacts will be relatively short-term (i.e. within the life-time of the grant itself) while we expect others to be medium- to long-term in nature. The PI and industry advisory panel, populated with world leading industry consultants, with recognised track records in antibiotic discovery, and senior representatives from current pharma partners, will ensure that impact activities are considered and acted upon throughout the project. This will provide exceptional opportunities to engage with industry and through workshops to expand this across the wider academic community.
Extension of a unique multidisciplinary multi-institutional training environment in cell wall biosynthesis to a wide cohort of students will be another important impact, including the development of training across the antibiotic discovery pipeline with a clear industry focus and specialist input from our industry consultants. The results will be of widespread academic and pharmaceutical interest, because of almost all efforts to date on PBP inhibition have focused on beta-lactams.
We have unprecedented support from global pharma, from PhD support to running screens and providing access to probe compounds, and engaging as members of our exceptional scientific advisory panel. All have a strong interest in using the pre-competitive information that will be generated. To help achieve this engagement we have well defined objectives and routes for further exploitation.
We have help from a political consultant to help engage and inform regional and national government alongside national activities with Antibiotic Research UK, Antibiotic Action and Antibiotic Discovery UK, and international activities via the Pew Trust and the Wellcome Trust.
This proposal brings together a globally unique group of recognised world leaders in complementary aspects of bacterial biochemistry, chemistry, genetics, physics and physiology in the area of peptidoglycan metabolism, structure and architecture. Our aim is to build from this proposal a nationally integrated, multi-centre, multidisciplinary programme of research to address the critical and unresolved understanding of PBPs in relevant Gram negative and Gram positive pathogens that is essential for future antibiotic discovery.
This will extend key competencies and capabilities of academia to support and engage effectively with the global biotechnology and pharmaceutical sector. As such the project will have diverse impacts within the UK and internationally. Some of the expected impacts will be relatively short-term (i.e. within the life-time of the grant itself) while we expect others to be medium- to long-term in nature. The PI and industry advisory panel, populated with world leading industry consultants, with recognised track records in antibiotic discovery, and senior representatives from current pharma partners, will ensure that impact activities are considered and acted upon throughout the project. This will provide exceptional opportunities to engage with industry and through workshops to expand this across the wider academic community.
Extension of a unique multidisciplinary multi-institutional training environment in cell wall biosynthesis to a wide cohort of students will be another important impact, including the development of training across the antibiotic discovery pipeline with a clear industry focus and specialist input from our industry consultants. The results will be of widespread academic and pharmaceutical interest, because of almost all efforts to date on PBP inhibition have focused on beta-lactams.
We have unprecedented support from global pharma, from PhD support to running screens and providing access to probe compounds, and engaging as members of our exceptional scientific advisory panel. All have a strong interest in using the pre-competitive information that will be generated. To help achieve this engagement we have well defined objectives and routes for further exploitation.
We have help from a political consultant to help engage and inform regional and national government alongside national activities with Antibiotic Research UK, Antibiotic Action and Antibiotic Discovery UK, and international activities via the Pew Trust and the Wellcome Trust.
Organisations
- University of Warwick (Lead Research Organisation, Project Partner)
- Bicycle Therapeutics (Collaboration)
- Newcastle University (Collaboration, Project Partner)
- UNIVERSITY OF OXFORD (Collaboration)
- University of Indianapolis (Collaboration)
- University of Amsterdam (Collaboration)
- University of Washington (Collaboration)
- University of Cape Town (Collaboration)
- MSD (United States) (Project Partner)
- University of Sheffield (Project Partner)
- Micropathology Ltd (Project Partner)
- AstraZeneca (United Kingdom) (Project Partner)
- Debiopharm (Switzerland) (Project Partner)
- Defence Science and Technology Laboratory (Project Partner)
- Chemical Biology Ventures (Project Partner)
- Novartis (Switzerland) (Project Partner)
- Basilea Pharmaceutica (Switzerland) (Project Partner)
- AstraZeneca (United States) (Project Partner)
- Cubist Pharmaceuticals (United States) (Project Partner)
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

Ashraf KU
(2022)
Structural basis of lipopolysaccharide maturation by the O-antigen ligase.
in Nature

Banzhaf M
(2020)
Outer membrane lipoprotein NlpI scaffolds peptidoglycan hydrolases within multi-enzyme complexes in Escherichia coli
in The EMBO Journal

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

Betts J
(2016)
In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo ß-lactamases
in MedChemComm

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

Bottomley AL
(2017)
Coordination of Chromosome Segregation and Cell Division in Staphylococcus aureus.
in Frontiers in microbiology
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 | 1) Understanding resistant bacteria in the context of the host (AMR Theme 1), 2) Accelerating therapeutics and diagnostics development (AMR Theme 2), 3) Understanding real world interactions (AMR Theme 3), 4) Behaviour within and beyond the healthcare setting (AMR Theme 4) |
Amount | £4,035,701 (GBP) |
Funding ID | MRF-145-0004-TPG-AVISO |
Organisation | Medical Research Council (MRC) |
Department | Medical Research Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2017 |
End | 01/2023 |
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 | Cefepime sulbactem MUTATE |
Amount | £54,490 (GBP) |
Funding ID | 64095 |
Organisation | Antibiotic Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2023 |
Description | Coventry General Charities |
Amount | £157,000 (GBP) |
Organisation | General Charity of the City of Coventry |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2018 |
End | 09/2022 |
Description | Coventry General Charities |
Amount | £90,000 (GBP) |
Organisation | University of Warwick |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2022 |
End | 03/2023 |
Description | Innovation Scholar |
Amount | £83,774 (GBP) |
Funding ID | MR/W003554/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2021 |
End | 09/2023 |
Description | Japan-UK AMR - fostering the next generation of antibiotic discovery |
Amount | £1,600,000 (GBP) |
Organisation | The Great Britain Sasakawa Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2023 |
End | 11/2029 |
Description | Multiscale characterization of complex materials using a combination of atomic force microscopy and optical coherence tomography |
Amount | £487,050 (GBP) |
Funding ID | EP/R025606/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 04/2020 |
Description | Newton UK china ANMR hubs |
Amount | £3,000,000 (GBP) |
Funding ID | MR/S014934/1 |
Organisation | University of Warwick |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2019 |
End | 12/2021 |
Description | Private Philanthropy |
Amount | £1,700,000 (GBP) |
Organisation | University of Warwick |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2022 |
End | 08/2026 |
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 | The bacterial cell wall in life and death |
Amount | £1,649,282 (GBP) |
Funding ID | 212197/Z/18/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2019 |
End | 01/2024 |
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 | Wellcome Trust Pathfinder Award |
Amount | £100,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2016 |
End | 03/2017 |
Title | Automated analysis of LC-MS/MS PG fragments |
Description | We have reported a novel strategy using shotgun proteomics techniques for a systematic and unbiased structural analysis of peptidoglycan fragments using high-resolution mass spectrometry and automated analysis of HCD and ETD fragmentation spectra with the Byonic software. |
Type Of Material | Technology assay or reagent |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | The strategy described allows a non-biased, ultra sensitive and rapid analysis of peptidoglycan LC-MS/MS data. We have published the proof of concept of this approach and demonstrated that it has the potential to detect an unexpected diversity of peptidoglycan structures. This will allow to elucidate the role of a large number of enzymes involved in peptidoglycan remodelling previously unknown. Thanks to the completeness of the method developed, we can now envisage to study in great details how peptidoglycan structure changes following treatment by cell wall targeting antibiotics or during pathogenesis. Thanks to this breakthrough, we can now envisage studying very dilute peptidoglycan samples (for example, from individual abscesses or in individual organs from infected animals such as mice). This is expected to reduce the number of animals required to carry out such studies. |
Title | Flow cytometry assay to quantify single-cell binding of proteins to bacterial cell surfaces |
Description | Using the high throughput flow cytometer purchased with the funding, we have developed an assay which allows quantification of protein binding to bacterial cells. We have now set up the proof of concept with using a single LysM peptidoglycan binding domain (LysMA1) as a model. This assay invloves: - LysM labelling; covalent FITC or a translational fusion with a fluorescent protein can be used - incubation in the presence of cells - measurement of fluorescence associated with individual cells by flow cytometry We have defined the conditions (protein concentrations, cell densities, buffer conditions, flow cytometry parameters) which give a binding dose-response to saturation. |
Type Of Material | Technology assay or reagent |
Year Produced | 2018 |
Provided To Others? | No |
Impact | This assay is instrumental to quantify protein-peptidoglycan interactions. It will allow us to measure the impact of peptidoglycan structure and cell wall components on binding (using isogenic mutants as substrates). We will also be able to compare the binding affinity of distinct LysM domains to the same cells. Beyond this project, this represents a technique widely applicable to any surface protein. |
Title | Virtual Reality - Touching proteins with bare hands |
Description | It is currently common practice among medicinal chemists while attempting the above to access the information contained in three-dimensional structures by using two-dimensional projections, which can preclude disclosure of useful features. A more accessible and intuitive visualization of the three-dimensional configuration of the atomic geometry in the models can be achieved through the implementation of immersive virtual reality (VR). While bespoke commercial VR suites are available, in this work, we present a freely available software pipeline for visualising protein structures through VR. New consumer hardware, such as the HTC VIVE and the OCULUS RIFT utilized in this study, are available at reasonable prices. As an instructive example, we have combined VR visualization with fast algorithms for simulating intramolecular motions of protein flexibility, in an effort to further improve structure-led drug design by exposing molecular interactions that might be hidden in the less informative static models. |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Outreach in public engagement and use by the wider research community |
URL | https://link.springer.com/article/10.1007/s10822-018-0123-0 |
Title | Staphylococcus aureus cell wall structure and dynamics during host-pathogen interaction |
Description | This is the raw data supporting the findings (both main text and supplementary) for our manuscript "Staphylococcus aureus cell wall structure and dynamics during host-pathogen interaction". Each excel file contains the raw data for each figure. Murine work was carried out according to UK law in the Animals (Scientific Procedures) Act 1986, under Project License P3BFD6DB9 (Staphylococcus aureus and other pathogens, pathogenesis to therapy, University of Sheffield Review Board). |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://figshare.shef.ac.uk/articles/dataset/Staphylococcus_aureus_cell_wall_structure_and_dynamics_... |
Description | H3D drug discovery University of Cape Town |
Organisation | University of Cape Town |
Country | South Africa |
Sector | Academic/University |
PI Contribution | Input of reagents assays and protein structures |
Collaborator Contribution | Input of medicinal chemistry know-how and chemical matter |
Impact | Interpersonal exchange of postdocs and to be PhD students |
Start Year | 2017 |
Description | Jeanne Salje |
Organisation | University of Oxford |
Department | Wolfson College |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | This is a scientific collaboration with Jeanne Salje on pathogenic intracellular bacterial. We contributed our expertise in bacterial cell wall structure and biosynthesis. |
Collaborator Contribution | The partner contributed their expertise in the biology of intracellular bacteria. |
Impact | Publication in scientific journal: PMID: 29178391 |
Start Year | 2017 |
Description | Joe Gray |
Organisation | Newcastle University |
Department | Newcastle University Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a long-term scientific collaboration with Joe Gray on bacterial cell walls and proteins. We contributed our expertise in bacterial cell wall structure and biosynthesis, provided research tools and performed experiments. |
Collaborator Contribution | The partner contributed their expertise in mass spectrometry for the analysis of bacterial cell walls and proteins, provided research tools and performed experiments. |
Impact | Publications in scientific journals: PMID: 31916938 PMID: 31209025 PMID: 30713527 PMID: 30102748 PMID: 30066424 PMID: 29311645 PMID: 28974693 PMID: 28581639 PMID: 27506799 PMID: 26537571 PMID: 26010014 PMID: 25424554 PMID: 24292151 PMID: 18996994 |
Start Year | 2007 |
Description | Joseph Mougous |
Organisation | University of Washington |
Department | Division of Medical Genetics |
Country | United States |
Sector | Academic/University |
PI Contribution | Expertise in bacterial cell wall. Experiments to determine peptidoglycan composition and enzymatic assays of peptidoglycan enzymes. |
Collaborator Contribution | Expertise in a the molecular biology of a variety of bacterial species, and in bacterial secretion systems. Experimental work on bacterial secretion systems. |
Impact | Scientific publications: PMID: 28696203 PMID: 25470067 PMID: 23878199 PMID: 22813741 PMID: 22607806 PMID: 21776080 |
Start Year | 2011 |
Description | Michael VanNieuwenhze |
Organisation | University of Indianapolis |
Country | United States |
Sector | Academic/University |
PI Contribution | This is a long-term scientific collaboration with Michael VanNieuwenhze on bacterial cell wall synthesis. We contributed our expertise in bacterial cell wall structure and biosynthesis, provided research tools and performed experiments. |
Collaborator Contribution | The partner contributed their expertise in chemical probes for bacterial cell wall labelling, provided research tools and performed experiments. |
Impact | Multi-disciplinary collaboration: chemistry, microbiology Publications in scientific journals: PMID: 31916938 PMID: 31743648 PMID: 31419110 PMID: 30504892 PMID: 30275297 PMID: 30233559 PMID: 30046664 PMID: 29765094 PMID: 29311645 PMID: 28974693 PMID: 24292151 |
Start Year | 2014 |
Description | Oxfrod chemistry |
Organisation | University of Oxford |
Department | Chemistry Research Laboratory |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have discussed this project and set up a collaboration with Professor Chris Schofield at Oxford to look at the affinity of beta-lactam dimers and polymers with Beta-lactamase enzymes. |
Collaborator Contribution | They will provide access to equipment and reagents to support this collaboration as well as host the student |
Impact | too early |
Start Year | 2017 |
Description | Paula Salgado |
Organisation | Newcastle University |
Department | Newcastle 85+ Study |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a scientific collaboration with Paula Salgado on the biochemistry of cell wall enzymes based on our common interest in the bacterial cell wall. We contributed our expertise in bacterial cell wall structure and biosynthesis, provided research tools and performed experiments. |
Collaborator Contribution | The partner contributed their expertise in the biology and sporulation in chlostridia, and x-ray crystallography, provided research tools and performed experiments. . |
Impact | Publication in peer reviewed journal: PMID: 30066424 |
Start Year | 2014 |
Description | Rick Lewis |
Organisation | Newcastle University |
Department | Newcastle University Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a long-term scientific collaboration with Rick Lewis on bacterial cell wall proteins. We contributed our expertise in bacterial cell wall structure and biosynthesis, provided research tools and performed experiments. |
Collaborator Contribution | The partner contributed their expertise in x-ray crystallography for the analysis for protein structure determination, provided research tools and performed experiments. |
Impact | Publications in scientific journals: PMID: 27862967 PMID: 27329754 PMID: 27257764 PMID: 25403286 PMID: 24954617 PMID: 24909784 PMID: 22432711 PMID: 21964069 PMID: 19074383 |
Start Year | 2007 |
Description | SME collaboration |
Organisation | Bicycle Therapeutics |
Country | United Kingdom |
Sector | Private |
PI Contribution | Knowledge Transfer Fundamental molecular microbiology and mechanistic understanding Reagents and assays |
Collaborator Contribution | PhD suport, internship support, reagent support, financial support |
Impact | Joint Innovate Uk Anti-Infectives funding https://www.bicycletherapeutics.com/beyond-oncology/ |
Start Year | 2018 |
Description | Tanneke den Blaauwen |
Organisation | University of Amsterdam |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | This is a long-term scientific collaboration with Tanneke den Blaauwen on cell envelope biogenesis in E. coli. We contribute our expertise in bacterial cell wall structure and biosynthesis, provided research tools and performed experiments. |
Collaborator Contribution | The partner contributed their expertise in bacterial cell biogenesis and cellular localization of proteins, provided research tools and performed experiments. |
Impact | Publications in scientific journals: PMID: 30233559 PMID: 26124755 PMID: 25951518 PMID: 23387922 PMID: 22606933 PMID: 21472954 PMID: 21183073 PMID: 20545860 PMID: 16803586 |
Title | BYOS (suite of mass spectrometry software customized for automated peptidoglycan analysis) |
Description | In collaboration with ProteinMetrics (https://www.proteinmetrics.com/), we are trying to customize available software solutions for peptidoglycan analysis. This has been facilitated by a BBSRC iCASE studentship (2017-2021). The source code has been modified to improve both the annotation of spectra and scoring method of peptidoglycan fragments (2017-2018). We are currently working towards a complete automated process whereby several software solutions are combined to provide a comprehensive analysis of MS1 and MS2 data as well as a quantification of peptidoglycan fragments. Since October 2018, we have generated a dedicated software which can predict fragmentation products from any peptidoglycan fragment using a graphic representation of molecules. This is being tested with Clostridium difficile peptidoglycan as a model system. |
Type Of Technology | Software |
Year Produced | 2019 |
Impact | The use of shotgun proteomics is a novel approach allowing an unbiased analysis of peptidoglycan structure. The automated approach we are developping has opened the possibility to carry out relatively high-throughput peptidoglycan analyses, currently impossible due to the labour-intensive methods available. |
Description | 10 Downing Street 2018 Chinese New Year Celebrations |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | Invitation from the PM to attend event to showcase UK China collaborative AMR research |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.gov.uk/government/news/pm-hosts-chinese-new-year-reception-at-downing-street |
Description | 1st RSC Prize lecture, Reading |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | "Remarkable Enzymes - from Bacteria to Humans" |
Year(s) Of Engagement Activity | 2019 |
Description | 2022-2023 Warwick Chemical Biology Lecture |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | This lectureship aims to bring leading Chemical Biologists to the University of Warwick to deliver a seminar on their research and spend the day discussing science with faculty and students |
Year(s) Of Engagement Activity | 2023 |
URL | https://warwick.ac.uk/fac/sci/chemistry/ |
Description | BBSRC Strategic Partnership Visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | A team from the BBSRC executive visited the University on 10 May 2018 as a part of our strategic partnership. More than 70 Warwick staff from various departments joined in the open sessions. Presentation of Research and Virtual Reality system |
Year(s) Of Engagement Activity | 2018 |
URL | https://warwick.ac.uk/fac/sci/lifesci/intranet/staffpg/support/comms/slsupdate/sls_update_june_2018.... |
Description | BSAC ARM Meeting, Birmingham |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | "Can the beta-lactams be beaten?" |
Year(s) Of Engagement Activity | 2019 |
Description | Cambridge Infectious Diseases Annual symposium |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Combating infectious diseases remains as important as ever. A combination of basic and applied research has historically led to some extraordinary success stories, such as the eradication of smallpox. Yet, recent events remind us that the emergence of a new infectious disease can rapidly traverse contents and threaten the health of the population on a global scale. With a society fighting a viral pandemic and the increasing concern of drug-resistant pathogens, infectious disease researchers face plenty of challenges that require coordinated networks of scientists and institutions. Title: Connecting Synthetic Chemistry and Clinically Relevant Microbiology |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.infectiousdisease.cam.ac.uk/programme-cid-annual-symposium-2023 |
Description | China UK People to People Exchange Royal Society December 6th 2017 |
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 | As PI for the CHNUK research grant I represent the wider UK-China AMR programme at the UK China People to People Dialogue in London on 6 December at the Royal Society. There was space for 15 of the highest profile collaborations and the FCO recommended the programme as a whole, but specifically that the CHNUK to be featured. As described by the FCO at the time "The programme is obviously a key part of the UK's current portfolio of research collaborations, and the exhibition stands need to be visual. A lot of the other stands will be full of robots and other toys so I need something that would stand out, having seen some of the X-ray crystallography images I thought this might be eye catching enough. There will be a walk through of the exhibition by UK and Chinese Ministers, including Madame Liu Yandong and hopefully Greg Clark on their way in to the building and hopefully they will stop and talk to several of the exhbitors and do photos but we don't know what will catch their eye just yet. You would be free to join the rest of the event after the Ministers have left, perhaps a colleague could attend the stand during the breaks etc." |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.gov.uk/government/topical-events/uk-china-high-level-people-to-people-dialogue-2017 |
Description | Croucher Advanced Study Institute 2021 - Metals in Biology and Medicine: From Molecular Imaging to Drug Resistance |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Study participants or study members |
Results and Impact | This course aims to disseminate the cutting-edge research about metals in biology and medicine to Hong Kong. The exploration of metals in biology and medicine is a fast-growing research area. Over the past decades, copper, iron and zinc have attracted enormous attentions due to the involvement of metals in aging and neuroscience. These metals can be detected and monitored in vivo by multi-techniques and multi-omics approaches, which further our understanding in metal homeostasis and metals in pathophysiological processes. This workshop aims to share some insightful views and ideas in molecular imaging and biosensing, metals in medicine, antibiotics and drug resistance |
Year(s) Of Engagement Activity | 2021 |
URL | https://chemistry.hku.hk/events/seminars_conferences_detail/175/ |
Description | Danish Society for Medicinal Chemistry and Chemical Biology Symposium |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | This full day symposium builds on the successful inaugural symposium in 2018. Jointly organised by the Danish Society for Medicinal Chemistry and Chemical Biology and the Center for Medicinal Chemistry at the University of Copenhagen, the meeting features and takes place in Haderup Auditorium 4, Panum Institute, Blegdamsvej 3B, 2100 Copenhagen. Title: Enmetazobactam and the mechanisms of widely used ß-lactamase inhibitors |
Year(s) Of Engagement Activity | 2023 |
URL | http://dsmkb.dk/en/symposium-jan-27th-2023/ |
Description | EU-UK science relations and Pasteur Bicentenary |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | The importance of chemistry in antibiotic discovery, EU-UK science relations and Pasteur Bicentenary, London, 2022 |
Year(s) Of Engagement Activity | 2022 |
URL | https://royalsociety.org/science-events-and-lectures/2022/10/pasteur-bicentenary-tribute/ |
Description | Establishment of Medicines discovery Catapult Facility |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | World-class technology and expertise are now available to UK drug discovery companies as a result of new laboratory facilities developed by the Medicines Discovery Catapult - launched on Wednesday 29th March at the University of Warwick. Catapult open for business with £1m investment in cutting-edge lab capacity to support UK drug discovery https://warwick.ac.uk/newsandevents/pressreleases/catapult_open_for/ |
Year(s) Of Engagement Activity | 2017 |
URL | https://vimeo.com/211376977 |
Description | Institute of Pharmaceutical Science - IPS Seminar Series - King's College London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | The seminars, hosted by Principal Investigators within the Departments, serve as a knowledge transfer and ideas exchange hub for researchers and academics within IPS, in addition to fostering new collaborations within and outside the Institute at a national and international level. Title 'Metalloenzymes- from mechanisms to medicines' |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.kcl.ac.uk/events/series/institute-of-pharmaceutical-science-seminar-series |
Description | International symposium on anti-TB biology and therapeutics |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | International symposium on anti-TB biology and therapeutics Title 'Metalloenzymes- from mechanisms to medicines' |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.medicilon.com/market-activities/anti-tb-symposium-2023/ |
Description | Liverpool Med Chem Symposium, Liverpool |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | "Is it possible to beat the beta-lactams?" |
Year(s) Of Engagement Activity | 2019 |
Description | MRC Milennium Medal Showcase of AMR research Palace of Westminster |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Presentation of MRC and RCUK funded AMR research to Peers and Politicians at the Palace of Westminster as part of the 2018 MRC Millennium Medal Award event |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.youtube.com/watch?v=n2Z6Xxs8aA0 |
Description | Natural Products, Students Against Superbugs Africa (SASA) webinar on AMR and drug development, 2021 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Study participants or study members |
Results and Impact | Students Against Superbugs (SAS) Africa is a student-driven initiative under the guidance of qualified health professionals which seeks to mitigate the threat of Antimicrobial Resistance (AMR) in African communities using a One Health Approach with a keen focus on rural areas and urban informal settlements. We do this by empowering young people throughout Africa to be lead advocates in the fight against AMR. Young people account for majority of the population and are the future global leaders and stakeholders. Their active participation will play a huge role in curtailing this health burden. It is imperative that they are made aware of it early enough, and nurtured to help in transiting appropriate knowledge, attitudes, and practices to their respective communities. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.studentsagainstsuperbugs.org/ |
Description | PPU-Oxford Bilateral Summit Program, "Chimie Biologique" - Linking Chemistry and Microbiology to fight human Infectious Diseases |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Study participants or study members |
Results and Impact | o Making antibiotics is easy, making useful ones is difficult French Institute of the United Kingdom, 2022 |
Year(s) Of Engagement Activity | 2022 |
URL | https://research.pasteur.fr/en/event/2nd-ppu-oxford-bilateral-summit-chimie-biologique-linking-chemi... |
Description | Participation in Launch of UKRI China, Beijing |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | Impact and breadth of UK-China collaboration on show at China launch of UK Research and Innovation Virtual Reality Display taken to Beijing to introduce our research and participate with event https://www.ukri.org/news/impact-and-breadth-of-uk-china-collaboration-on-show-at-china-launch-of-uk-research-and-innovation/ Video clip of AMTR activities presented at event - see below |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.ukri.org/research/international/ukri-international-offices/ukri-china/ |
Description | Pint of Science public outreach |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Pint of Science is an annual science festival that takes place every May and brings researchers to your local pub to present their scientific discoveries. |
Year(s) Of Engagement Activity | 2018 |
URL | https://pintofscience.co.uk/event/life-is-the-name-of-the-game |
Description | Press release + interview BBC Sheffield to comment on published article (Salamaga et al., PLoS Pathogens, 2017) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Following the publication of the research article (Salamaga et al.,2017), a press release has been published by the university of Sheffield media team. This led to an interview with BBC Sheffield (31/07/2017), an article in the national media support Metro ("killer bug too small for antibiotics"), an article in AOL online and international media (India and Taiwan). |
Year(s) Of Engagement Activity | 2016,2017 |
Description | Public Science Event Warwick University |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | On Thursday 26 April 2018, the School of Life Sciences hosted its fourth public science evening of the 2017/18 academic year (the ninth since the programme began in 2016). This evening was a panel discussion focussing on three topics of interest, highlighted by the public from previous public science evenings. These were: Epigenetics, Environment & Sustainability and Medical Microbiology |
Year(s) Of Engagement Activity | 2018 |
URL | https://warwick.ac.uk/fac/sci/lifesci/intranet/staffpg/support/comms/slsupdate/sls_update_june_2018.... |
Description | Radio 4 3 part drama production |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Radio drama highlighting factors driving antibiotic resistance and global consequences - raising public awareness at the National level |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.bbc.co.uk/programmes/b08g7y1l |
Description | Radley College Lecture |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Lecture topic - From Penicillins to Sensing Oxygen |
Year(s) Of Engagement Activity | 2021 |
Description | SMi Superbugs and Superdrugs Conference, London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Study participants or study members |
Results and Impact | "Strategies to Combat ß-lactamases" |
Year(s) Of Engagement Activity | 2019 |
Description | Towards world changing antibiotics, Janssen Research & Development, WHO World Antimicrobial Awareness Week, 2021 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | World Antimicrobial Awareness Week (WAAW) is celebrated from 18-24 November every year. The 2021 theme, Spread Awareness, Stop Resistance, called on One Health stakeholders, policymakers, health care providers, and the general public to be Antimicrobial Resistance (AMR) Awareness champions. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.who.int/campaigns/world-antimicrobial-awareness-week/2021 |
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 | UKRI Superheroes vs Superbugs live at the Science Museum |
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 | On 25 April, leading researchers from the MRC and UK research councils will join the Science Museum's free, adults-only, late opening of the Superbugs: The Fight for Our Livesopens in new window exhibition. The exhibition, which is sponsored by UKRI, looks at the causes and challenges of antimicrobial resistance (AMR), and why previously effective drugs are no longer winning the battle against some infections. Mega Magnification - Be transported into the hidden world of bacteria. Use VR to shrink yourself, meet mighty bacterial proteins and reveal their microscopic secrets. |
Year(s) Of Engagement Activity | 2018 |
URL | https://mrc.ukri.org/news/browse/ukri-superheroes-vs-superbugs-live-at-the-science-museum/ |
Description | Uppsala University, Sweden |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Study participants or study members |
Results and Impact | 'From penicillins to epigenetics' |
Year(s) Of Engagement Activity | 2019 |