Repurposing the phospholipase A2 inhibitor, darapladib, to combat multidrug-resistant fungal pathogens, including Candida auris

Candida auris is an emerging multidrug-resistant fungal pathogen and a major global health threat, highlighting the urgent need for new therapeutics. We screened ~2,600 FDA-approved drugs and clinical compounds and identified darapladib (DAL), a phospholipase A2 inhibitor, as a potent antifungal agent against multidrug-resistant C. auris. DAL exhibited antifungal activity against all tested C. auris isolates and showed broad-spectrum activity against other tested clinically important fungal pathogens, including other Candida, Cryptococcus, and mucormycosis-associated species, with minimum inhibitory concentrations of 4-16 μg/mL. DAL also displayed rapid fungicidal activity against C. auris and synergized with amphotericin B against C. auris and filamentous fungal pathogens. More importantly, serial exposure of C. auris to subinhibitory concentrations of DAL for 16 passages did not result in detectable resistance. Mechanistic studies indicated that DAL acts through an ergosterol-dependent membrane targeting mechanism, as exogenous ergosterol attenuated its activity and ergosterol-related haploinsufficient mutants showed reduced susceptibility. Consistent with this mechanism, DAL increased membrane permeability, nucleic acid leakage, and reactive oxygen species. In a Caenorhabditis elegans-C. auris infection model, DAL reduced the C. auris burden to below the limit of detection. Together, these findings support further investigation of DAL as a repurposed antifungal candidate against drug-resistant fungal infections.