Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids

Polymyxins are a class of lipopeptide anti-infective
agents with
potent and specific activity against Gram-negative bacteria. While
toxicity concerns associated with polymyxin B and E (colistin) have
historically limited their clinical application, today they are increasingly
used as last-resort antibiotics given the rise of multidrug-resistant
Gram-negative pathogens. The adverse side effects of polymyxins are
well known, particularly as related to their nephrotoxicity. Here,
we describe the synthesis and evaluation of a novel series of polymyxin
analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic
approach, we explored modifications of the exocyclic part of the polymyxin
scaffold, namely, the terminal amino acid and lipophilic tail. By
incorporating a reductively labile disulfide linkage in the lipid
tail, we obtained novel polymyxins that exhibit potent antibacterial
activity on par with polymyxin B but with reduced toxicity toward
human renal proximal tubular epithelial cells.