Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity

Abstract

A novel series of polymyxin analogues bearing a disulfide linked lipid tail are reported. The most promising variant identified exhibits antibacterial activity equipotent to that of polymyxin B and is >10-fold less toxic towards kidney cells.

Recent Advances in the Development of Polymyxin Antibiotics: 2010–2023

“…These findings suggest that the inclusion of disulfide-linked lipids may indeed provide a means to tune the metabolic stability of polymyxins in pursuit of analogues with reduced toxicity. Building from these findings we also recently reported a second generation of disulfide linked analogues based on 18d wherein the P3 residue was varied . This led to the identification of analogue 8d , bearing l -Dap at P3, as an improved variant with potent antibacterial activity and even lower cytotoxicity toward PTECs (Table ).…”

“…With the aim of generating less toxic analogues, our group recently developed a series of novel polymyxin B variants bearing N -terminal lipids containing a reductively labile disulfide bond as well as modifications at P1 and P3 (Figure ). , Based on previous studies indicating that the lipid tail contributes significantly to the toxic effects associated with the polymyxins, we envisioned intracellular cleavage of the disulfide-linked lipid as a means of addressing this toxicity. Given the highly reducing environment found inside kidney cells, we hypothesized that upon renal uptake, subsequent disulfide reduction could in turn lead to formation of less toxic and/or more rapidly cleared metabolites.…”

“…Building from these findings we also recently reported a second generation of disulfide linked analogues based on 18d wherein the P3 residue was varied. 134 This led to the identification of analogue 8d , bearing l -Dap at P3, as an improved variant with potent antibacterial activity and even lower cytotoxicity toward PTECs ( Table 2 ).…”