Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal.

ABSTRACT: Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model¹. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers^2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bi

SUBMITTER: Maji A 

PROVIDER: S-EPMC10883201 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature