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

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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.