Cytochrome bc1 Catalytic Subunit Rip1 Modulates Antifungal Tolerance in Candida auris

Candida auris is an emerging fungal pathogen causing invasive infections in immunocompromised patients, with mortality rates reaching up to 60%. Pronounced drug resistance makes treatment failure common, and so does antifungal tolerance, a phenomenon enabling pathogen survival at supra-MIC concentrations without resistance mutations. Here, we uncover a mechanism of antifungal tolerance in C. auris engaging the mitochondrial cytochrome bc1 complex. Deletion of RIP1, a conserved catalytic complex subunit, does not significantly alter the susceptibility to caspofungin or voriconazole. However, rip1Δ mutants exhibit a marked reduction in antifungal tolerance across a wide range of supra-MIC concentrations. Transcriptomics reveals the dysregulation of multiple drug resistance and tolerance-related genes in the rip1Δ mutant, demonstrating a role for Rip1 in controlling antifungal susceptibility. Targeting cytochrome bc1 function with the fungal-specific inhibitor Inz-5 enhances antifungal action of both voriconazole and caspofungin. Additionally, ablation of RIP1 causes fitness defects, suggesting that cytochrome bc1 is a potential antifungal target against C. auris infections.