One size fits all: The semi-synthesis of new undecaprenol analogues for the study of multiple undecaprenyl-processing enzymes

Antibacterial resistance is a major threat to human health and there is a pertinent need for new antimicrobial targets. Bacteria produce several glycopolymers that are vital to their survival, including peptidoglycan, which is a key component of the bacterial cell wall required for structural integrity. The bacterial cell wall is targeted by many clinically used antibiotics, such as penicillin and vancomycin. Glycopolymer biosynthesis involves several key glycolipid intermediates, all of which are linked to the cell membrane by the molecule undecaprenol. The enzymes that process undecaprenol-linked biomolecules are hot antibiotic targets, as they are unique to bacteria. However, detailed studies on these enzymes and the high-throughput screening of possible inhibitors has been limited due to the lack of suitable probes to monitor their activity. An understanding of enzyme mechanism is a vital pre-requisite to the rationale design of inhibitors. This project aims to develop new labelled analogues of undecaprenol, which will be used to study several novel antibiotic targets and provide a method for the high-throughput screening of potential antibiotic candidates.

Economic Impact - A healthy nation places less of a financial strain on the National Health Service. In the UK Review on Antimicrobial Resistance (2015) it was estimated that if left unchecked, AMR will cost the global economy up to $100 trillion due to extended hospital stays and treatment. Our tools to study potential antibiotic targets could facilitate the development of new antibiotics, reducing the economic cost of AMR and allowing tax money to be spent on other public services. Labelled undecaprenol probes are highly sought after as tools to understand life-processes. There is a market for cheaper undecaprenol and new undecaprenyl probes. Given that we can produce multi-gram quantities of undecaprenol and similar quantities of the proposed undecaprenyl probes, our research could lead to commercial products that increase UK tax revenue.

Societal Impact - AMR is perhaps the biggest problem our generation will face, with new resistance mechanisms increasing and deaths due to AMR on the rise. Our approach to synthesize new undecaprenyl probes will allow the study of any undecaprenyl-processing enzyme, which could yield new antimicrobial targets and compounds. After the successful synthesis of the undecaprenyl probes, we will initiate collaborations with world-leading experts to better understand the mechanism of these enzymes and develop in vitro assays to screen antibiotic candidates. We will reach out to companies to share our results and gain access to compound libraries for screening with our assays.

Academic Impact - The EPSRC has identified the importance of growing the area of Chemical Biology and Biological Chemistry to establish UK excellence in this area. This project will provide a highly-skilled researcher in Chemical Biology through the training of a postdoctoral research associate (PDRA). The PDRA will receive expert training in all aspects of organic synthesis, molecular biology and microbiology. They will also develop management skills as they oversee the day-to-day activities of more junior lab members. By completion of this project, a new highly-skilled researcher in Chemical Biology will enter the UK workforce and their training will make them highly employable in an industrial or academic setting, where they will go on to train more researchers with the skills they have developed.

Personal Impact - Receiving this New Investigator Award will be highly beneficial to the principal investigator (PI), providing vital early support that will allow his career to flourish, leading to the future training of many more students and PDRAs. The results generated from this project will lead to future funding applications through EPSRC and elsewhere, as well as facilitate the development of new collaborations with both academic and industrial partners.