Chen et al. identify the natural product butyrolactol A as an inhibitor of the phospholipid flippase Apt1-Cdc50, which it locks in a nonfunctional state. By disrupting membrane homeostasis and enhancing drug uptake, butyrolactol A restores echinocandin efficacy against intrinsically resistant fungal pathogens, including Cryptococcus and Candida auris.