UK-BaCWAN: UK-Bacterial Cell Wall Assembly Network

Lead Research Organisation: University of Warwick
Department Name: Biological 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 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.

The group at Warwick has brought together a UK-wide team from microbiology, biochemistry, chemistry, structural biology, physiology, engineering and mathematics to crack this problem. 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

Bacterial cell wall assembly is an important target for the development of novel antibacterial agents, and is intimately connected with the emergence of antibiotic resistance around the world. There are significant research programmes carried out in UK laboratories in this area, but at present these activities are somewhat fragmented, with groups in Chemistry, Biochemistry, and Microbiology departments following different areas related to this problem. Therefore we propose to establish a UK Network in bacterial cell wall assembly, which can bring together expertise different disciplines and provide a forum for the additional involvement of industrial and physical scientists, to inform the network of industrial interests and emerging physical techniques. 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. The establishment of a web site to distribute 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

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Batson S (2010) Crystallization and preliminary X-ray analysis of a D-alanyl-D-alanine ligase (EcDdlB) from Escherichia coli. in Acta crystallographica. Section F, Structural biology and crystallization communications

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Li Q (2015) Full-length structure of the major autolysin LytA. in Acta crystallographica. Section D, Biological crystallography

 
Description AWM-Science City, Translational Medicine
Amount £229,138 (GBP)
Organisation Advantage West Midlands 
Sector Public
Country United Kingdom
Start 01/2009 
End 01/2014
 
Description BBSRC Project Grant
Amount £410,114 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2011 
End 05/2014
 
Description CIHR-MRC Network Funding
Amount £30,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description MRC project grant
Amount £731,794 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2011 
End 04/2014
 
Description teamCanUK: Novel antibacterial targets, assays, probes and oportunities in bacterial cell wall biogenesis
Amount £1,261,509 (GBP)
Funding ID G1100127 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 01/2016
 
Title BACWAN Website and peptidoglycan synthesis facility 
Description website: www.warwick.ac.uk/go/bacwan 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact The research materials provided by the BACWAN synthetic facility provide much needed and high value intermediates required for bacterial cell wall research. 
URL http://www2.warwick.ac.uk/fac/sci/lifesci/people/droper/bacwan/
 
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 School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Web cast detailing research activity of the interdisciplinary group at Warwick supported by MRC fundinghttp://www2.warwick.ac.uk/newsandevents/pressreleases/research_could_put. Subsequent press release was reported all over the world

Invitation to scientific meetings and policy making events.
Year(s) Of Engagement Activity 2008