Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

Tanvi Shekhar-Guturja; G. M.Kamal B. Gunaherath; E. M.Kithsiri Wijeratne; Jean Philippe Lambert; Anna F. Averette; Soo Chan Lee; Taeyup Kim; Yong Sun Bahn; Farida Tripodi; Ron Ammar; Katja Döhl; Karolina Niewola-Staszkowska; Lutz Schmitt; Robbie J. Loewith; Frederick PRoth; Dominique Sanglard; David Andes; Corey Nislow; Paola Coccetti; Anne Claude Gingras; Joseph Heitman; AALeslie Gunatilaka; Leah ECowen

doi:10.1038/nchembio.2165

Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

Tanvi Shekhar-Guturja, G. M.Kamal B. Gunaherath, E. M.Kithsiri Wijeratne, Jean Philippe Lambert, Anna F. Averette, Soo Chan Lee, Taeyup Kim, Yong Sun Bahn, Farida Tripodi, Ron Ammar, Katja Döhl, Karolina Niewola-Staszkowska, Lutz Schmitt, Robbie J. Loewith, Frederick PRoth, Dominique Sanglard, David Andes, Corey Nislow, Paola Coccetti, Anne Claude GingrasJoseph Heitman, AALeslie Gunatilaka, Leah ECowen

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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.

Original language	English
Pages (from-to)	867-875
Number of pages	9
Journal	Nature Chemical Biology
Volume	12
Issue number	10
DOIs	https://doi.org/10.1038/nchembio.2165
Publication status	Published - 2016 Oct 1

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1038/nchembio.2165

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Shekhar-Guturja, T., Gunaherath, G. M. K. B., Wijeratne, E. M. K., Lambert, J. P., Averette, A. F., Lee, S. C., Kim, T., Bahn, Y. S., Tripodi, F., Ammar, R., Döhl, K., Niewola-Staszkowska, K., Schmitt, L., Loewith, R. J., PRoth, F., Sanglard, D., Andes, D., Nislow, C., Coccetti, P., ... ECowen, L. (2016). Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. Nature Chemical Biology, 12(10), 867-875. https://doi.org/10.1038/nchembio.2165

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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.",

author = "Tanvi Shekhar-Guturja and Gunaherath, {G. M.Kamal B.} and Wijeratne, {E. M.Kithsiri} and Lambert, {Jean Philippe} and Averette, {Anna F.} and Lee, {Soo Chan} and Taeyup Kim and Bahn, {Yong Sun} and Farida Tripodi and Ron Ammar and Katja D{\"o}hl and Karolina Niewola-Staszkowska and Lutz Schmitt and Loewith, {Robbie J.} and Frederick PRoth and Dominique Sanglard and David Andes and Corey Nislow and Paola Coccetti and Gingras, {Anne Claude} and Joseph Heitman and AALeslie Gunatilaka and Leah ECowen",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",

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doi = "10.1038/nchembio.2165",

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Shekhar-Guturja, T, Gunaherath, GMKB, Wijeratne, EMK, Lambert, JP, Averette, AF, Lee, SC, Kim, T, Bahn, YS, Tripodi, F, Ammar, R, Döhl, K, Niewola-Staszkowska, K, Schmitt, L, Loewith, RJ, PRoth, F, Sanglard, D, Andes, D, Nislow, C, Coccetti, P, Gingras, AC, Heitman, J, Gunatilaka, AAL & ECowen, L 2016, 'Dual action antifungal small molecule modulates multidrug efflux and TOR signaling', Nature Chemical Biology, vol. 12, no. 10, pp. 867-875. https://doi.org/10.1038/nchembio.2165

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AU - Gunaherath, G. M.Kamal B.

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AU - Lambert, Jean Philippe

AU - Averette, Anna F.

AU - Lee, Soo Chan

AU - Kim, Taeyup

AU - Bahn, Yong Sun

AU - Tripodi, Farida

AU - Ammar, Ron

AU - Döhl, Katja

AU - Niewola-Staszkowska, Karolina

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AU - PRoth, Frederick

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AU - Andes, David

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AU - Heitman, Joseph

AU - Gunatilaka, AALeslie

AU - ECowen, Leah

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Y1 - 2016/10/1

N2 - 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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Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

Abstract

Bibliographical note

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UN SDGs

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