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; Tripodi, Farida; Ammar, Ron; Döhl, Katja; Niewola-Staszkowska, Karolina; Schmitt, Lutz; Loewith, Robbie Joséph; Roth, Frederick P; Sanglard, Dominique; Andes, David; Nislow, Corey; Coccetti, Paola; Gingras, Anne-Claude; Heitman, Joseph; Gunatilaka, A A Leslie; Cowen, Leah E

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Title		Dual action antifungal small molecule modulates multidrug efflux and TOR signaling
Authors		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 Tripodi, Farida Ammar, Ron Döhl, Katja Niewola-Staszkowska, Karolina Schmitt, Lutz Loewith, Robbie Joséph Roth, Frederick P Sanglard, Dominique Andes, David Nislow, Corey Coccetti, Paola Gingras, Anne-Claude Heitman, Joseph Gunatilaka, A A Leslie Cowen, Leah E show all authors [1 - 23]
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/metabolism — Antifungal Agents/chemistry/pharmacology — Depsipeptides/chemical synthesis/chemistry/pharmacology — Drug Resistance — Fungal/drug effects — Drug Resistance — Multiple/drug effects — Fungi/drug effects/metabolism — HSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolism — Microbial Sensitivity Tests — Mycoses/drug therapy/microbiology — Protein Kinase Inhibitors/chemical synthesis/chemistry/pharmacology — Saccharomyces cerevisiae Proteins/genetics/metabolism — Signal Transduction/drug effects — Small Molecule Libraries/chemistry/pharmacology — TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
Identifiers		DOI: 10.1038/nchembio.2165 PMID: 27571477
Full text		Article (Published version) (2.3 MB) - Limited access to UNIGE Other version: https://www.nature.com/articles/nchembio.2165
Structures		Faculté des sciences / Section de biologie / Département de biologie moléculaire Centres et instituts / Institut de génétique et de génomique
Research group		Groupe Loewith
Citation (ISO format)		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. https://archive-ouverte.unige.ch/unige:103221