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

抗击抗菌素耐药性是我们这一代人面临的最重大挑战之一。细菌对临床抗生素不断产生新的耐药机制，使感染更加难以治疗。因此，迫切需要新的抗菌化合物和靶点。Brevicidine和laterocidine是抗菌肽，对多重耐药的革兰氏阴性细菌有很强的活性，革兰氏阴性细菌是一类更难杀死的细菌，因为它们有额外的细胞膜。它们甚至对抗粘菌素的革兰氏阴性菌有活性，粘菌素是我们目前的最后一种抗生素。因此，这些肽可能是很好的抗生素候选物。然而，它们很难通过化学合成来制备，并且不像其他类型的环肽那样稳定，并且它们杀死细菌的机制尚不清楚。本项目旨在开发更稳定、更容易制备并具有增强抗菌活性的新型布雷维西定和红血球西定类似物。我们还将确定它们如何杀死细菌，如果这些肽要成为抗生素，这是很重要的知识。

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.