期刊
NATURE CHEMICAL BIOLOGY
卷 12, 期 10, 页码 867-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2165
关键词
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资金
- Ontario Graduate Scholarship
- University of Toronto Open Fellowship
- Canadian Institutes of Health Research (CIHR) Operating Grants [MOP-86452, MOP-119520]
- Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grants [06261, 462167]
- NSERC E.W.R. Steacie Memorial Fellowship [477598]
- Canada Research Chair in Microbial Genomics and Infectious Disease
- DUKE PO1 [AI104533-01]
- RO1 [AI112595-02]
- General International Collaborative R&D program - Ministry of Trade, Industry and Energy (MOTIE) in Republic of Korea [N0001720]
- US Institutes of Health Grants [R01 CA090265, P41 GM094060]
- CIHR Foundation Grant
- Genome Canada Genomics Innovation Network (GIN) Node and Technical Development Grants
- Canada Research Chair in Functional Proteomics
- CIHR
- TD Bank Health Research Fellowship at the Lunenfeld-Tanenbaum Research Institute
- Italian Government
- MIUR
- Ministry of Trade, Industry & Energy (MOTIE), Republic of Korea [N0001720] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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