Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

The polymyxin lipodecapeptides colistin
and polymyxin B have become
last resort therapies for infections caused by highly drug-resistant
Gram-negative bacteria. Unfortunately, their utility is compromised
by significant nephrotoxicity and polymyxin-resistant bacterial strains.
We have conducted a systematic activity–toxicity investigation
by varying eight of the nine polymyxin amino acid free side chains,
preparing over 30 analogues using a novel solid-phase synthetic route.
Compounds were tested against a panel of Gram-negative bacteria and
counter-screened for in vitro cell toxicity. Promising
compounds underwent additional testing against primary kidney cells
isolated from human kidneys to better predict their nephrotoxic potential.
Many of the new compounds possessed equal or better antimicrobial
potency compared to polymyxin B, and some were less toxic than polymyxin
B and colistin against mammalian HepG2 cells and human primary kidney
cells. These initial structure–activity and structure–toxicity
studies set the stage for further improvements to the polymyxin class
of antibiotics.