Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.

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.
Mesh Terms:
ATP-Binding Cassette Transporters, Antifungal Agents, Depsipeptides, Drug Resistance, Fungal, Drug Resistance, Multiple, Fungi, HSP90 Heat-Shock Proteins, Microbial Sensitivity Tests, Mycoses, Protein Kinase Inhibitors, Saccharomyces cerevisiae Proteins, Signal Transduction, Small Molecule Libraries, TOR Serine-Threonine Kinases
Nat. Chem. Biol.
Date: Oct. 01, 2016
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