Synthesis of novel brevicidine and laterocidine analogues active against multi-drug-resistant Gram-negative bacteria

Combatting antimicrobial resistance is one of the most significant challenges facing our generation. Bacteria are relentlessly developing new resistance mechanisms against clinical antibiotics, making infections much harder to treat. Therefore, there is an urgent need for new antimicrobial compounds and targets. Brevicidine and laterocidine are antimicrobial peptides that have strong activity against multidrug-resistant Gram-negative bacteria, a class of bacteria that are much harder to kill as they have an extra cell membrane. They are even active against Gram-negative organisms resistant to colistin, our current antibiotic of last resort. Therefore these peptides could be excellent antibiotic candidates. However, they are difficult to prepare by chemical synthesis and less stable than other types of cyclic peptides, and the mechanism by which they kill bacteria is not known. This project aims to develop new brevicidine and laterocidine analogues that are more stable, easier to prepare and have enhanced antimicrobial activity. We will also determine how they kill bacteria, which is important knowledge if these peptides are to become antibiotics.

Economic Impact - Improving the health of the UK population will place less of a financial burden on the National health Service. Jim O'Neill's report on the cost of antimicrobial resistance by 2050 paints a worrying picture, both in terms of premature deaths (up to 10 million per year) and the global economy ($100 trillion spent by 2050). This project will facilitate the development of new antibiotics, reducing the economic cost of antimicrobial resistance and allowing tax money to be allocated to other public services.

Societal Impact - Antimicrobial resistance is one of the greatest problems facing our generation, with new resistance mechanisms continually emerging and deaths due to antimicrobial resistance on the rise. Our research will yield important mechanistic information about novel antibiotic compounds that could aid rational drug design. We will synthesise a large library of antimicrobial peptides through this project and the most promising candidates will be taken forward for further study through avenues such as the European Gram-Negative Antibacterial Engine (ENABLE) and sending compounds for advanced screening to the Community for Open Antimicrobial Drug Discovery (Co-ADD). As the project progresses, we will also make use of industrial engagement funding at QUB to identify project-partners who may be interested in further development of the antimicrobial compounds generated through this project.

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 - With his previous award of an EPSRC New Investigator Award and publication of independent research articles and communications, the PI has demonstrated his ability to produce high-quality science with a small research group and resources. To achieve his ambition of becoming a world-leader in the development of novel antimicrobial compounds and targets, a larger research group and resources will be required. The addition of another PDRA and PhD student (QUB leverage studentship) to the Cochrane lab will allow more high-impact research to be performed and published, allowing the PI to develop a global reputation and further his career.