Tools and Reagents for Next Generation Inhibitor Discovery in Peptidoglycan biosynthesis

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Antimicrobial resistance to existing antibiotics threatens future healthcare at multiple levels and has been acknowledged as a worldwide issue with an impact as important as climate change. However, a number of factors has led to a steady decline in the discovery and development of antimicrobials in the pharmaceutical industry despite the clear clinical need. The remaining pharmaceutical company antibacterial research and development in this area has focused generally in the past on either attempts to discover new targets for antibiotics or new compounds with limited activity profiles based on existing targets. Generally this approach has met with very limited success which combined with other factors, means we have a decreasing number of drugs to treat bacterial infection leading to a crisis in healthcare. It is clear that bacteria are adept at the selection of resistance to drugs for single gene targets (i.e. their protein products) and that the successful antimicrobial chemotherapy of the past, selects biological processes where there are multiple essential activities e.g. protein synthesis at the ribosome, the proteins which are responsible for DNA supercoiling in the cell and mechanisms by which formation and cross-linking of the bacterial cell wall polymer is achieved. The biosynthesis of the bacterial cell wall polymer called peptidoglycan is an excellent target for antimicrobials in this respect since it provides an opportunity for multi-targeting as described above, is not a structure found in animals or humans so there is less chance of adverse chemical sensitivity and the process occurs outside the cell allowing easier access for drug molecules. Whilst the penicillin group of drugs have been used to exploit these advantages in the past, they target the cross-linking activity of the bacterial enzymes concerned. These enzymes, called penicillin binding proteins, are also responsible for the formation of the peptidoglycan polymer as well in a completely separate reaction that has hitherto been under explored as a target for antibiotics.Our proposal seeks to gain the essential knowledge required to explore these enzymes for next generation antibiotics. Our proposal links the knowledge and advances in academia and industry in a mutually beneficial effort to get the key information required. Critically, we need to generate a series of specialist chemical probes to interrogate the mechanism by which these enzymes work, to determine the structures of these probes bound to the enzymes to generate new assays that will allow the discovery of future antibiotics.