Synthesis, Antibacterial Activity, and Nephrotoxicity of Polymyxin B Analogues Modified at Leu-7, <scp>d</scp>-Phe-6, and the N-Terminus Enabled by S-Lipidation
Paul W. R. Harris, Andrew Siow, Sung‐Hyun Yang, Andrew D. Wadsworth, Lyndia Tan, Yann O. Hermant, Yubing Mao, Chalice An, Cameron C. Hanna, Alan J. Cameron, Jane R. Allison, Aparajita Chakraborty, Scott Ferguson, Sonya Mros, Kiel Hards, Gregory M. Cook, Deborah A. Williamson, Glen P. Carter, Susanna T. S. Chan, Gavin F. Painter, Veronika Sander, Alan J. Davidson, Margaret A. Brimble
Abstract
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.