Summary

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 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 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 the 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.