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

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.

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.