UK-BaCWAN2: Continuation and Expansion of UK-Bacterial Cell Wall Assembly Network
Lead Research Organisation:
University of Sheffield
Department Name: Molecular Biology and Biotechnology
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 now 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, by using the advanced computing power at our disposal to design new classes of antibiotics, compounds that will work against multiply resistant bacteria like MRSA, and help combat the harmful effects of our immune system when it over responds to infection.
BACWAN consists of a group of scientists from academia, industry and government whose goals is increase and coordinate activity in his area to bring about new treatments and strategies. They will have, for the first time, the combined tools and new chemical reagents (to be made for the team at a cost efficient central location at Warwick) to look in minute detail how peptidoglycan is made, how we could stop this process by the development of new inhibitors (antibiotics) and how fragments of peptidoglycan interact with our bodies during the process of infection. This capacity for discovery, being lost elsewhere, will provide a unique forum for the development of new compounds.
BACWAN consists of a group of scientists from academia, industry and government whose goals is increase and coordinate activity in his area to bring about new treatments and strategies. They will have, for the first time, the combined tools and new chemical reagents (to be made for the team at a cost efficient central location at Warwick) to look in minute detail how peptidoglycan is made, how we could stop this process by the development of new inhibitors (antibiotics) and how fragments of peptidoglycan interact with our bodies during the process of infection. This capacity for discovery, being lost elsewhere, will provide a unique forum for the development of new compounds.
Technical Summary
The process of assembly of the bacterial cell wall is a validated and important target for the development of novel antibacterial agents, and is intimately connected with the emergence of antibiotic resistance around the world. Significant research programmes in this area are carried out in UK laboratories, but at present these activities are somewhat fragmented, between groups in Chemistry, Physics, and Biology departments following different areas related to this problem. Our existing UK Network in bacterial cell wall assembly, has been successful in bringing together some of these groups with expertise in different disciplines and provide a forum for the additional involvement of industrial and healthcare associated scientists, to inform the network of industrial interests and emerging techniques and areas of interest. We now wish to capitalise and expand upon this network by recruiting further members and promoting excellent scientific collaboration. The principal vehicle for this network will be a series of bi-yearly meetings involving chemists, biochemists, microbiologists, computational, industrial and physical scientists to stimulate new inter-disciplinary research and collaboration in this area. Our website provides a useful additional level of information for our members and distributes information to members, other scientists and the general public will also augment these meetings. We also wish to facilitate new collaborative research programmes that will arise from this network by funding inter-laboratory and interdisciplinary visits for students, postdoctoral researchers and PIs, enabling technology and technique transfer to stimulate future research efforts within the UK scientific community.
Publications

Alderwick LJ
(2008)
Expression, purification and characterisation of soluble GlfT and the identification of a novel galactofuranosyltransferase Rv3782 involved in priming GlfT-mediated galactan polymerisation in Mycobacterium tuberculosis.
in Protein expression and purification

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

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

Clarke TB
(2009)
Mutational analysis of the substrate specificity of Escherichia coli penicillin binding protein 4.
in Biochemistry

Cressina E
(2009)
Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors.
in Bioorganic & medicinal chemistry

De Pascale G
(2008)
Kinetic characterization of lipid II-Ala:alanyl-tRNA ligase (MurN) from Streptococcus pneumoniae using semisynthetic aminoacyl-lipid II substrates.
in The Journal of biological chemistry

Hong HJ, Hutchings MI, Buttner MJ
(2008)
Advances in Experimental Medicine and Biology

Kawai F
(2010)
Crystal structures of penicillin-binding proteins 4 and 5 from Haemophilus influenzae.
in Journal of molecular biology

Lloyd AJ
(2008)
Characterization of tRNA-dependent peptide bond formation by MurM in the synthesis of Streptococcus pneumoniae peptidoglycan.
in The Journal of biological chemistry

Paradis-Bleau C
(2009)
Pseudomonas aeruginosa MurE amide ligase: enzyme kinetics and peptide inhibitor.
in The Biochemical journal
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 | 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 | A novel actinomycete strain from the soil microbiome defends monoculture strawberry against Fusrium wilt |
Organisation | Gyeongsang National University |
Department | Department of Applied Biology |
Country | Korea, Republic of |
Sector | Academic/University |
PI Contribution | We provided the knowledge and technology for the general aspect of molecular microbiology of actinomycete strain. |
Collaborator Contribution | Dr Kwak's group in Gyeonsang National University has initially isolated the actinomycete strain which was responsible for a disease-suppressive soil activity and performed all the field study. |
Impact | We recently submitted the manuscript with other collaborators into Nature. |
Start Year | 2012 |
Description | Canada |
Organisation | University of Guelph |
Country | Canada |
Sector | Academic/University |
PI Contribution | Research presentations and ideas |
Collaborator Contribution | A UK Canada consortium in the area of Bacterial Cell Walls. Mutual collaborative visits have been made. |
Impact | Joint grant applications |
Start Year | 2009 |
Description | Research Collaboration |
Organisation | Newcastle University |
Department | Institute for Cell and Molecular Biosciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research Collaboration |
Collaborator Contribution | Research collaboration leading to future grant applicationsResearch collaboration, student exchange |
Impact | Joint grant applications |
Start Year | 2008 |
Description | Research Collaboration |
Organisation | University of Birmingham |
Department | College of Life and Environmental Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research Collaboration |
Collaborator Contribution | Research collaboration leading to future grant applicationsResearch collaboration, student exchange |
Impact | Joint grant applications |
Start Year | 2008 |
Title | Peptidoglycan intermediates availible to Scientific community |
Description | The BACWAN synthetic facility has developed a range of peptidoglycan intermediates that are available to the scientific community for use in research and assay development |
Type | Support Tool - For Medical Intervention |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2008 |
Development Status | Under active development/distribution |
Impact | These intermediates are already having an impact on advancing the development of novel assays and routes for antibiotic discovery as well as basic science |
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 | Press release |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Web cast and press release outlining work at Warwick and wider network Invitation to speak, further public understanding of science presentations |
Year(s) Of Engagement Activity | 2008 |
Description | School Visit - Hathersage |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Primary Audience | Schools |
Results and Impact | Introduction to microbiology. This included oral and practical sessions. No subsequent impact |
Year(s) Of Engagement Activity | 2009 |
Description | School Visit Shrewsbury |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Primary Audience | Schools |
Results and Impact | Schools visit and promotion Invitation to return |
Year(s) Of Engagement Activity | 2009 |