Synthetic Studies with the Brevicidine and Laterocidine Lipopeptide Antibiotics Including Analogues with Enhanced Properties and in vivo Efficacy.

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 assay and in vivo infection models.