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, Leslie Gunatilaka, Leah ECowen

Research output: Contribution to journalArticle

29 Scopus citations

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 languageEnglish (US)
Pages (from-to)867-875
Number of pages9
JournalNature Chemical Biology
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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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