Abstract
Given that many antifungal medications are susceptible to evolved resistance, there is a need for novel drugs with unique mechanisms of action. Inhibiting the essential proton pump Pma1p, a P-type ATPase, is a potentially effective therapeutic approach that is orthogonal to existing treatments. We identify NSC11668 and hitachimycin as structurally distinct antifungals that inhibit yeast ScPma1p. These compounds provide new opportunities for drug discovery aimed at this important target.
Highlights
Antifungal medications are in high demand, but low efficacy, host toxicity, and emerging resistance among clinical strains [1, 2] complicate their use
We recently discovered that KAE609, an antimalarial compound currently in Phase II clinical trials [16], is cytotoxic to S. cerevisiae and inhibits ScPma1p by binding to the cytoplasm-accessible pocket [17]
In summary, we have identified NSC11668 and hitachimycin as antifungal molecules that target ScPma1p, a transmembrane protein crucial for pH homeostasis in fungal pathogens [14]
Summary
Antifungal medications are in high demand, but low efficacy, host toxicity, and emerging resistance among clinical strains [1, 2] complicate their use. There is an urgent need for novel antimycotic therapeutics with unique mechanisms of action. Most antifungals in clinical use target ergosterol, a sterol present in fungal membranes but largely absent from human cells [3]. Polyene antimycotics bind directly to ergosterol, thereby destabilizing the membrane [4]. Allylamines inhibit squalene monooxygenase [5], the first enzyme in the ergosterol biosynthetic pathway [6]. Most azole antifungals inhibit the downstream enzyme lanosterol 14 α-demethylase [7], with the possible exception of abafungin, which may instead affect
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