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Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

Nature Chemical Biology volume 12, pages 867–875 (2016)Cite this article

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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.

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Figure 1: Beauvericin enhances azole efficacy against diverse fungi and blocks the emergence of resistance.
Figure 2: Beauvericin inhibits Pdr5, thereby increasing fluconazole intracellular accumulation, and can be effluxed by Pdr5 following substitutions that alter substrate specificity.
Figure 3: Whole-genome sequencing of beauvericin-resistant mutants identifies mutations in protein kinase CK2.
Figure 4: Beauvericin binds to protein kinases Tor2 and CK2 and modulates their activity.
Figure 5: Beauvericin inhibits Hsp90 function.
Figure 6: The combination of beauvericin and fluconazole provides a powerful therapeutic strategy.

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Acknowledgements

We thank the Donnelly Sequencing Centre for whole genome sequencing; the 2013 MGY360H1 class for performing and analyzing whole-genome sequencing data for a subset of the resistant mutants in the ABC16 background; D. Kim for assistance with genome sequencing analysis of the resistant mutants in the yor1Δ background; and all members of the Cowen lab for discussions. T.S.-G. is supported by the Ontario Graduate Scholarship and University of Toronto Open Fellowship. L.E.C. is supported by the Canadian Institutes of Health Research (CIHR) Operating Grants (MOP-86452 and MOP-119520), the Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grants (06261 and 462167), an NSERC E.W.R. Steacie Memorial Fellowship (477598), and a Canada Research Chair in Microbial Genomics and Infectious Disease. J.H. is supported by the DUKE PO1 (AI104533-01) and RO1 (AI112595-02) for antifungal drug discovery. Y.-S.B is supported by the General International Collaborative R&D program funded by Ministry of Trade, Industry and Energy (MOTIE) in Republic of Korea (N0001720). A.A.L.G. is supported by US Institutes of Health Grants (R01 CA090265 and P41 GM094060). A.-C.G. is supported by a CIHR Foundation Grant, Genome Canada Genomics Innovation Network (GIN) Node and Technical Development Grants, and a Canada Research Chair in Functional Proteomics. J.-P.L was supported by a postdoctoral fellowship from the CIHR and by a TD Bank Health Research Fellowship at the Lunenfeld–Tanenbaum Research Institute. P.C. is supported by the Italian Government (FA). F.T. is supported by a postdoctoral fellowship from MIUR.

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Authors and Affiliations

  1. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Tanvi Shekhar-Guturja, Frederick P Roth, Anne-Claude Gingras & Leah E Cowen

  2. Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, Arizona, USA

    G M Kamal B Gunaherath, E M Kithsiri Wijeratne & A A Leslie Gunatilaka

  3. Lunenfeld–Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Jean-Philippe Lambert, Frederick P Roth & Anne-Claude Gingras

  4. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA

    Anna F Averette, Soo Chan Lee, Taeyup Kim & Joseph Heitman

  5. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea

    Yong-Sun Bahn

  6. Department of Biotechnology and Biosciences, University of Milano–Bicocca and SYSBIO, Centre of Systems Biology, Milan, Italy

    Farida Tripodi & Paola Coccetti

  7. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada

    Ron Ammar

  8. Institute of Biochemistry, Heinrich Heine University Duesseldorf, Duesseldorf, Germany

    Katja Döhl & Lutz Schmitt

  9. Department of Molecular Biology, University of Geneva, Geneva, Switzerland

    Karolina Niewola-Staszkowska & Robbie J Loewith

  10. Institute of Microbiology, University Hospital Lausanne and University Hospital Center, Lausanne, Switzerland

    Dominique Sanglard

  11. Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA

    David Andes

  12. Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA

    David Andes

  13. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Corey Nislow

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  1. Tanvi Shekhar-Guturja
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Contributions

L.E.C. and T.S.-G. conceived of and designed the study. T.S.-G. designed and performed selection experiments, drug-susceptibility assays, qRT-PCR, β-galactosidase activity assays, and western blots. R.A. and C.N. analyzed whole-genome sequencing data for a subset of the beauvericin-resistant strains in the ABC16 background. F.P.R. analyzed whole-genome sequencing data for a subset of the beauvericin-resistant strains in the ABC16 background. D.S. designed and performed the azole accumulation experiment. L.S. and K.D. designed and performed the in vitro Pdr5 ATPase and rhodamine 6G transport assays. G.M.K.B.G., E.M.K.W., and A.A.L.G. synthesized the biotinylated beauvericin analog. A.-C.G. and J.-P.L. designed the AP–MS experiment; J.-P.L. performed and analyzed AP–MS data under supervision of A.-C.G. F.T. and P.C. designed and performed CK2 kinase activity assays. R.J.L. and K.N.-S. designed and performed experiments to monitor TORC1 and TORC2 activity via Sch9 and Ypk1 phosphorylation, respectively. Y.-S.B., A.F.A., and J.H. designed the C. albicans mouse study; Y.-S.B., A.F.A., S.C.L., T.K., and J.H. performed and analyzed the mouse study. D.A. designed and performed the C. albicans biofilm study.

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Correspondence to Leah E Cowen.

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Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–4 and Supplementary Figures 1–12. (PDF 14000 kb)

Supplementary Note 1

Isolation of beauvericin (1) and synthesis of biotinyloxybeauvericin (PDF 600 kb)

Supplementary Note 2

Plasmid and strain construction (PDF 320 kb)

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Shekhar-Guturja, T., Gunaherath, G., Wijeratne, E. et al. Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. Nat Chem Biol 12, 867–875 (2016). https://doi.org/10.1038/nchembio.2165

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