Synergistic antifungal effects and potential mechanisms 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.