Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, BlocksC. albicansMorphogenesis, and is Effluxed via Yor1 and Circuitry Controlled by Zcf29
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 using the natural product beauvericin against leading human fungal pathogens. We found that beauvericin potentiates the activity of azole antifungals against azole-resistantCandidaisolates via inhibition of multidrug efflux, and that beauvericin itself is effluxed via Yor1. As observed inSaccharomyces cerevisiae, we determined that beauvericin inhibits TOR signaling inCandida albicans. To further characterize beauvericin activity inC. albicans, we leveraged genome sequencing of beauvericin-resistant mutants. Resistance was conferred by mutations in transcription factor genesTAC1,which is a key regulator of multidrug efflux, andZCF29, 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 theC. albicansmorphogenetic 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 factorBRG1. 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.