Synthesis and Biological Evaluation of the Complete Octapeptin Natural Product Series

The octapeptins are a set of 18 closely related natural
product
cyclic lipopeptides with broad spectrum activity against Gram-negative
bacteria, including polymyxin-resistant strains. Within this class,
only four congeners have been synthesized and/or tested in pure form,
prompting us to investigate all 18 individual members. Here, we describe
their chemical synthesis, which required the preparation of a series
of chiral β-hydroxy fatty acids followed by solid-phase peptide
synthesis and solution-phase cyclization. The series was tested against
a panel of polymyxin-sensitive and -resistant Gram-negative pathogens,
with minimum inhibitory concentrations of 2–8 μg/mL for
most members. Oct-B5 and Oct-C0, two analogues possessing structural
features disparate from those of the rest of the series, were shown
to be inactive against the same panel of bacteria. Antifungal activity
was also tested. This study demonstrates the first systematic synthesis
and antimicrobial testing of a complete set of octapeptin natural
product lipopeptides.