Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

作者：Shekhar Guturja Tanvi; Gunaherath G M Kamal B; Wijeratne E M Kithsiri; Lambert Jean Philippe; Averette Anna F; Lee Soo Chan; Kim Taeyup; Bahn Yong Sun; Tripodi Farida; Ammar Ron; Doehl Katja; Niewola Staszkowska Karolina; Schmitt Lutz; Loewith Robbie J; Roth Frederick P; Sanglard Dominique; Andes David; Nislow Corey; Coccetti Paola; Gingras Anne Claude; Heitman Joseph; Gunatilaka A A Leslie; Cowen Leah E

来源：Nature Chemical Biology, 2016, 12(10): 867-+.

DOI：10.1038/NCHEMBIO.2165

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for treating fungal infectious disease that evades resistance.

• 出版日期2016-10