Synergistic antifungal effects and potential mode of action of crisaborole combined with azoles against drug-resistant Candida albicans.

BACKGROUND

Candida albicans is the leading pathogen of life-threatening invasive candidiasis, with mortality exceeding 40% in immunocompromised patients. Global azole resistance and limited approved antifungal classes severely restrict clinical treatment, making repurposing FDA-approved drugs a promising low-barrier strategy.

RESEARCH DESIGN AND

METHODS

The synergistic antifungal activity of crisaborole (CRB) combined with azoles was validated via checkerboard microdilution assay. In vivo efficacy of CRB plus ketoconazole (KCZ) was evaluated in a Galleria mellonella infection model, with mechanisms explored via phenotypic assays and qPCR.

RESULTS

CRB combined with azoles exerted potent synergism against drug-resistant C. albicans (FICI 0.023-0.500). CRB+KCZ significantly improved larval survival, reduced fungal burden, inhibited fungal efflux pump activity, and impaired hyphal growth and host cell adhesion of C. albicans.

CONCLUSIONS

CRB specifically enhances azoles' antifungal activity, offering a clinically translatable therapeutic strategy for drug-resistant C. albicans infections.