title: Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, Blocks Candida albicans Morphogenesis, and Is Effluxed via Yor1 and Circuitry Controlled by Zcf29.
abstract: Invasive fungal infections are a leading cause of human mortality. Effective treatment is hindered by the rapid emergence of resistance to the limited number of antifungal drugs, demanding new strategies to treat life-threatening fungal infections. Here, we explore a powerful strategy to enhance antifungal efficacy against leading human fungal pathogens by using the natural product beauvericin. We found that beauvericin potentiates the activity of azole antifungals against azole-resistant Candida isolates via inhibition of multidrug efflux and that beauvericin itself is effluxed via Yor1. As observed in Saccharomyces cerevisiae, we determined that beauvericin inhibits TOR signaling in Candida albicans To further characterize beauvericin activity in C. albicans, we leveraged genome sequencing of beauvericin-resistant mutants. Resistance was conferred by mutations in transcription factor genes TAC1, a key regulator of multidrug efflux, and ZCF29, which was uncharacterized. Transcriptional profiling and chromatin immunoprecipitation coupled to microarray analyses revealed that Zcf29 binds to and regulates the expression of multidrug transporter genes. Beyond drug resistance, we also discovered that beauvericin blocks the C. albicans morphogenetic transition from yeast to filamentous growth in response to diverse cues. We found that beauvericin represses the expression of many filament-specific genes, including the transcription factor BRG1 Thus, we illuminate novel circuitry regulating multidrug efflux and establish that simultaneously targeting drug resistance and morphogenesis provides a promising strategy to combat life-threatening fungal infections.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Shekhar-Guturja
authors.affiliation: Department of Chemistry and Biochemistry, Concordia University, Montréal, Québec, Canada.
authors.forename: Walters Aji
authors.initials: WA
authors.lastname: Tebung
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Harley
authors.initials: H
authors.lastname: Mount
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Köhler
authors.affiliation: Department of Biology, Concordia University, Montréal, Québec, Canada.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whiteway
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada leah.cowen@utoronto.ca.
authors.forename: Leah E
authors.initials: LE
authors.lastname: Cowen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D001483:Base Sequence; D001688:Biological Products / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000235:genetics*; D004357:Drug Synergism; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D046228:Microarray Analysis; D009154:Mutation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D001393:Azoles; D001688:Biological Products; D047630:Depsipeptides; D005656:Fungal Proteins; D014157:Transcription Factors; C004456:beauvericin; D058570:TOR Serine-Threonine Kinases