Butyrolactol A potentiates caspofungin efficacy against resistant fungi via phospholipid flippase inhibition.

ABSTRACT: Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris, a notorious global threat, is also increasingly resistant. We performed a natural product extract screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris. Mode of action studies revealed that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1•butyrolactol A com

SUBMITTER: Chen X 

PROVIDER: S-EPMC11741340 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature