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Neofunctionalization of a P-type ATPase enables fluconazole efflux in Candida auris

ABSTRACT: Candida auris is an emerging fungal pathogen known for its high resistance to fluconazole, the most commonly prescribed antifungal. However, the genetic regulators of fluconazole susceptibility remain insufficiently understood in C. auris. Using a pooled screen of piggyBac (PB) transposition mutants, we identify significant enrichment of mitochondrial genes whose inactivation causes reduced fluconazole susceptibility. Genome-wide genetic interaction analysis of a representative mitochondrial gene-deleted mutant, pet309Δ, implicates that mitochondrial dysfunction reduces fluconazole susceptibility by enhancing Cdr1 efflux activity post-transcriptionally and through the vacuolar calcium pump homolog Cdt1. We further demonstrate that Cdt1, beyond its canonical calcium-pumping function, mediates fluconazole efflux, evidenced by its fluconazole-induced, calcineurin-dependent plasma membrane localization and dependence on ATP hydrolysis. Additionally, Cdt1 accelerates the evolution of fluconazole resistance, and its transcript levels correlate with susceptibility across clinical isolates. Our findings define a novel role for Cdt1 in fluconazole efflux in C. auris.

ORGANISM(S): Candidozyma auris

PROVIDER: GSE300783 | GEO | 2026/01/06

REPOSITORIES: GEO

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Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 M-BM-5g/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 M-BM-5g/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its cas5M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Cas5.

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Neofunctionalization of a P-type ATPase enables fluconazole efflux in Candida auris

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