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

The compound inhibited every C. auris isolate tested and showed broad-spectrum activity against other clinically important fungi, including other Candida species, Cryptococcus, and mucormycosis-associated fungi, with minimum inhibitory concentrations of 4 to 16 micrograms per milliliter. Beyond simply halting growth, darapladib displayed rapid fungicidal activity against C. auris and acted synergistically with amphotericin B, a key last-line antifungal, against both C. auris and filamentous fungal pathogens. Notably, serial exposure of C. auris to subinhibitory concentrations of the drug over 16 passages did not produce detectable resistance, an encouraging sign for a pathogen notorious for quickly developing multidrug resistance.

Mechanistic experiments pointed to an ergosterol-dependent membrane-targeting mode of action. Adding exogenous ergosterol, the fungal membrane sterol targeted by several existing antifungals, weakened darapladib's activity, and ergosterol-related haploinsufficient mutants showed reduced susceptibility. Consistent with membrane disruption, treatment increased fungal membrane permeability, triggered leakage of nucleic acids, and elevated production of reactive oxygen species inside the cells.

The team also tested the drug in a Caenorhabditis elegans infection model of C. auris. In this whole-animal system, darapladib treatment reduced the fungal burden to below the limit of detection, providing early preclinical evidence that the compound can combat infection in a living host, not only in laboratory cultures. The findings support further investigation of darapladib as a repurposed antifungal candidate for drug-resistant fungal infections.

Subject of Research: Repurposing the phospholipase A2 inhibitor darapladib as an antifungal agent against multidrug-resistant Candida auris and other fungal pathogens

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

Article References: Elgammal, Y., Salama, E. A., Alkashef, N. M., Lawrence, C. B., & Seleem, M. N. (2026). Repurposing the phospholipase A2 inhibitor, darapladib, to combat multidrug-resistant fungal pathogens, including Candida auris. PLOS One, 21(10), e0361366. https://doi.org/10.1371/journal.pone.0361366

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DOI: 10.1371/journal.pone.0361366

Keywords: Candida auris, darapladib, drug repurposing, antifungal resistance, phospholipase A2 inhibitor, ergosterol, amphotericin B, Caenorhabditis elegans, multidrug-resistant fungi, membrane permeability, Repurposing, phospholipase