Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.

Details

Serval ID
serval:BIB_BF502DCF92C9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.
Journal
Nature chemical biology
Author(s)
Shekhar-Guturja T., Gunaherath G.M., Wijeratne E.M., 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., Roth F.P., Sanglard D., Andes D., Nislow C., Coccetti P., Gingras A.C., Heitman J., Gunatilaka A.A., Cowen L.E.
ISSN
1552-4469 (Electronic)
ISSN-L
1552-4450
Publication state
Published
Issued date
10/2016
Peer-reviewed
Oui
Volume
12
Number
10
Pages
867-875
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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, 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, Signal Transduction/drug effects, Small Molecule Libraries/chemistry, Small Molecule Libraries/pharmacology, TOR Serine-Threonine Kinases/antagonists & inhibitors, TOR Serine-Threonine Kinases/metabolism
Pubmed
Create date
16/09/2016 18:45
Last modification date
20/08/2019 15:33
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