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Cytochrome bc1 Catalytic Subunit Rip1 Modulates Antifungal Tolerance in Candida auris
Trinh Phan-Canh1,2,3, Michaela Lackner3, Manju Chauhan4
1Max Perutz Laboratories Vienna, Vienna BioCenter Campus (VBC), Dr. Bohr-Gasse 9, 1030Vienna, Austria.
ACS Infectious Diseases
|July 30, 2026
Summary
The mitochondrial cytochrome bc1 complex, specifically the RIP1 subunit, is crucial for Candida auris antifungal tolerance. Inhibiting this complex enhances drug efficacy against this emerging fungal pathogen.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Molecular Biology
Background:
- Candida auris is a significant emerging fungal pathogen responsible for invasive infections, particularly in immunocompromised individuals.
- High mortality rates (up to 60%) and widespread antifungal drug resistance complicate treatment of C. auris infections.
- Antifungal tolerance, distinct from resistance, allows C. auris survival at higher drug concentrations, posing a therapeutic challenge.
Purpose of the Study:
- To investigate the molecular mechanisms underlying antifungal tolerance in Candida auris.
- To identify novel therapeutic targets for enhancing antifungal drug efficacy against C. auris.
Main Methods:
- Genetic manipulation of Candida auris, including deletion of the RIP1 gene encoding a subunit of the cytochrome bc1 complex.
- Assessment of fungal susceptibility and tolerance to various antifungal drugs (caspofungin, voriconazole) at sub- and supra-Minimum Inhibitory Concentrations (MICs).
- Transcriptomic analysis to identify gene expression changes in the rip1Δ mutant.
- Evaluation of a fungal-specific cytochrome bc1 inhibitor (Inz-5) in combination with existing antifungals.
Main Results:
- Deletion of RIP1 significantly reduced C. auris antifungal tolerance across a broad range of supra-MIC drug concentrations.
- Transcriptomic data revealed dysregulation of key drug resistance and tolerance genes in the rip1Δ mutant, highlighting Rip1's role.
- Inhibition of the cytochrome bc1 complex using Inz-5 potentiated the antifungal activity of both voriconazole and caspofungin.
- Ablation of RIP1 resulted in fitness defects in C. auris.
Conclusions:
- The mitochondrial cytochrome bc1 complex, particularly the Rip1 subunit, plays a critical role in mediating antifungal tolerance in Candida auris.
- Targeting the cytochrome bc1 complex represents a promising strategy to overcome antifungal tolerance and enhance treatment efficacy against C. auris.
- The findings suggest that cytochrome bc1 is a viable antifungal target for combating C. auris infections.
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