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Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

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
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Published in Nature chemical biology. 2016, vol. 12, no. 10, p. 867-875
Abstract 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.
Keywords ATP-Binding Cassette Transporters/genetics/metabolismAntifungal Agents/chemistry/pharmacologyDepsipeptides/chemical synthesis/chemistry/pharmacologyDrug ResistanceFungal/drug effectsDrug ResistanceMultiple/drug effectsFungi/drug effects/metabolismHSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolismMicrobial Sensitivity TestsMycoses/drug therapy/microbiologyProtein Kinase Inhibitors/chemical synthesis/chemistry/pharmacologySaccharomyces cerevisiae Proteins/genetics/metabolismSignal Transduction/drug effectsSmall Molecule Libraries/chemistry/pharmacologyTOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
PMID: 27571477
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Other version: https://www.nature.com/articles/nchembio.2165
Research group Groupe Loewith
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SHEKHAR-GUTURJA, Tanvi et al. Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. In: Nature chemical biology, 2016, vol. 12, n° 10, p. 867-875. doi: 10.1038/nchembio.2165 https://archive-ouverte.unige.ch/unige:103221

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Deposited on : 2018-03-27

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