1. Dual action antifungal small molecule modulates multidrug efflux and TOR signaling
- Author
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Soo Chan Lee, Anne-Claude Gingras, Joseph Heitman, Paola Coccetti, Corey Nislow, Karolina Niewola-Staszkowska, Ron Ammar, Katja Döhl, A. A. Leslie Gunatilaka, Anna F. Averette, Taeyup Kim, David R. Andes, Yong Sun Bahn, Lutz Schmitt, E. M. Kithsiri Wijeratne, G. M. Kamal B. Gunaherath, Frederick P. Roth, Dominique Sanglard, Leah E. Cowen, Robbie Loewith, Farida Tripodi, Tanvi Shekhar-Guturja, Jean-Philippe Lambert, Shekhar Guturja, T, Gunaherath, G, Wijeratne, E, Lambert, J, Averette, A, Lee, S, Kim, T, Bahn, Y, Tripodi, F, Ammar, R, Döhl, K, Niewola Staszkowska, K, Schmitt, L, Loewith, R, Proth, F, Sanglard, D, Andes, D, Nislow, C, Coccetti, P, Gingras, A, Heitman, J, Gunatilaka, A, and Ecowen, L
- Subjects
0301 basic medicine ,Antifungal Agents ,Mutant ,Drug Resistance ,Drug resistance ,Antifungal Agents/chemistry/pharmacology ,chemistry.chemical_compound ,ddc:590 ,Signal Transduction/drug effects ,Depsipeptides ,Mycoses/drug therapy/microbiology ,biology ,Kinase ,ATP-Binding Cassette Transporters/genetics ,ATP-Binding Cassette Transporters/metabolism ,Antifungal Agents/chemistry ,Antifungal Agents/pharmacology ,Depsipeptides/chemical synthesis ,Depsipeptides/chemistry ,Depsipeptides/pharmacology ,Drug Resistance, Fungal/drug effects ,Drug Resistance, Multiple/drug effects ,Fungi/drug effects ,Fungi/metabolism ,HSP90 Heat-Shock Proteins/antagonists & inhibitors ,HSP90 Heat-Shock Proteins/metabolism ,Microbial Sensitivity Tests ,Mycoses/drug therapy ,Mycoses/microbiology ,Protein Kinase Inhibitors/chemical synthesis ,Protein Kinase Inhibitors/chemistry ,Protein Kinase Inhibitors/pharmacology ,Saccharomyces cerevisiae Proteins/genetics ,Saccharomyces cerevisiae Proteins/metabolism ,Small Molecule Libraries/chemistry ,Small Molecule Libraries/pharmacology ,TOR Serine-Threonine Kinases/antagonists & inhibitors ,TOR Serine-Threonine Kinases/metabolism ,TOR Serine-Threonine Kinases ,Fungal/drug effects ,BIO/11 - BIOLOGIA MOLECOLARE ,Hsp90 ,BIO/10 - BIOCHIMICA ,Drug Resistance, Multiple ,3. Good health ,Biotinylation ,Protein Kinase Inhibitors/chemical synthesis/chemistry/pharmacology ,Efflux ,Signal Transduction ,Saccharomyces cerevisiae Proteins ,030106 microbiology ,Saccharomyces cerevisiae Proteins/genetics/metabolism ,Article ,Microbiology ,Fungi/drug effects/metabolism ,Small Molecule Libraries ,03 medical and health sciences ,Drug Resistance, Fungal ,ddc:570 ,Small Molecule Libraries/chemistry/pharmacology ,HSP90 Heat-Shock Proteins ,Molecular Biology ,Protein Kinase Inhibitors ,Cell Biology, antifungal small molecule, CK2 pathway,TOR signaling ,Fungi ,Cell Biology ,BIO/19 - MICROBIOLOGIA GENERALE ,Depsipeptides/chemical synthesis/chemistry/pharmacology ,TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism ,Beauvericin ,TOR signaling ,030104 developmental biology ,chemistry ,Mycoses ,biology.protein ,ATP-Binding Cassette Transporters/genetics/metabolism ,HSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolism ,ATP-Binding Cassette Transporters ,Multiple/drug effects - 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.
- Published
- 2015