Synthetic studies with the brevicidine and laterocidine lipopeptide antibiotics including analogues with enhanced properties and efficacy

• Published in: Chemical science (Cambridge) Vol. 13; no. 12; pp. 3563 - 357
• Main Authors: Al Ayed, Karol, Ballantine, Ross D, Hoekstra, Michael, Bann, Samantha J, Wesseling, Charlotte M. J, Bakker, Alexander T, Zhong, Zheng, Li, Yong-Xin, Brüchle, Nora C, van der Stelt, Mario, Cochrane, Stephen A, Martin, Nathaniel I
• Format: Journal Article
• Published: 24.03.2022
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d2sc00143h

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assays and in vivo infection models. Convenient solid-phase approaches are described for the synthesis of brevicidine and laterocidine. Also reported are novel analogues including a laterocidine variant with enhanced hydrolytic stability and potent in vivo antibacterial activity.