Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, Blocks Candida albicans Morphogenesis, and Is Effluxed via Yor1 and Circuitry Controlled by Zcf29
| Autor: | Ning-Ning Liu, Malcolm Whiteway, Harley O’Connor Mount, Walters Aji Tebung, Julia R. Köhler, Leah E. Cowen, Tanvi Shekhar-Guturja |
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| Rok vydání: | 2016 |
| Předmět: |
Azoles
0301 basic medicine Antifungal Agents Drug resistance Biology Microbiology Fungal Proteins 03 medical and health sciences chemistry.chemical_compound Drug Resistance Fungal Mechanisms of Resistance Depsipeptides Gene Expression Regulation Fungal Candida albicans Pharmacology (medical) Transcription factor Pharmacology Biological Products Fungal protein Base Sequence Gene Expression Profiling TOR Serine-Threonine Kinases Fungal genetics Drug Synergism Microarray Analysis biology.organism_classification Beauvericin Corpus albicans 030104 developmental biology Infectious Diseases chemistry Biochemistry Mutation ATP-Binding Cassette Transporters Efflux Signal Transduction Transcription Factors |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 60:7468-7480 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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