Synthesis, Antibacterial Activity, and Nephrotoxicity of Polymyxin B Analogues Modified at Leu-7, d-Phe-6, and the N-Terminus Enabled by S-Lipidation.

With the post-antibiotic era rapidly approaching, many have turned their attention to developing new treatments, often by structural modification of existing antibiotics. Polymyxins, a family of lipopeptide antibiotics that are used as a last line of defense in the clinic, have recently developed resistance and exhibit significant nephrotoxicity issues. Using thiol-ene chemistry, the facile preparation of six unique S-lipidated building blocks was demonstrated and used to generate lipopeptide mimetics upon incorporation into solid-phase peptide synthesis (SPPS). We then designed and synthesized 38 polymyxin analogues, incorporating these unique building blocks at the N-terminus, or to replace hydrophobic residues at positions 6 and 7 of the native lipopeptides. Several polymyxin analogues bearing one or more S-linked lipids were found to be equipotent to polymyxin, showed minimal kidney nephrotoxicity, and demonstrated activity against several World Health Organisation (WHO) priority pathogens. The S-lipidation strategy has demonstrated potential as a novel approach to prepare innovative new lipopeptide antibiotics.

Synthesis and SAR Analysis of Lipovelutibols B and D and Their Lipid Analogues.

The first syntheses of the cytotoxic peptides lipovelutibols B and D are described. While lipovelutibol D was prepared using solid-phase peptide synthesis followed by an O-N acyl migration to install the C-terminal amino alcohol, a different strategy was required to access lipovelutibol B and a series of N-terminal lipid analogues of the natural products. A cytotoxicity structure-activity relationship study revealed that the lipovelutibol D framework, whereby serine is substituted for alanine in the fifth position, provided the most potent analogues. Modification of the lipid tail was generally well tolerated, with longer alkyl chains enhancing analogue cytotoxicity.