Format

Send to

Choose Destination
Nat Chem Biol. 2016 Oct;12(10):867-75. doi: 10.1038/nchembio.2165. Epub 2016 Aug 29.

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

Author information

1
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
2
Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, Arizona, USA.
3
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
4
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
5
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
6
Department of Biotechnology and Biosciences, University of Milano-Bicocca and SYSBIO, Centre of Systems Biology, Milan, Italy.
7
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
8
Institute of Biochemistry, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
9
Department of Molecular Biology, University of Geneva, Geneva, Switzerland.
10
Institute of Microbiology, University Hospital Lausanne and University Hospital Center, Lausanne, Switzerland.
11
Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
12
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.
13
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.

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.

PMID:
27571477
PMCID:
PMC5030160
[Available on 2017-02-28]
DOI:
10.1038/nchembio.2165
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Statement The authors declare no competing financial interests.

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center