Floricolin C elicits intracellular reactive oxygen species accumulation and disrupts mitochondria to exert fungicidal action.

Candida albicans, one of the most prevalent fungal pathogens, causes severe mucosal and invasive infections in predisposed individuals. The rise of fungal infection and drug resistance demands the development of novel antifungal agents. In this study, we observed that floricolin C (FC), a p-terphenyl pigment from an endolichenic fungus, killed C. albicans cells in the planktonic state or within biofilms through reactive oxygen species (ROS) accumulation. Further tests revealed that FC could directly damage the mitochondria to cause ROS accumulation. In addition, FC can quench thiol-based agents through a Michael reaction involving the α,β-unsaturated carbonyl group, whose effect may chelate intracellular thiol-based molecules or proteins in C. albicans, resulting in an imbalance in redox homeostasis. Increased ROS generation led to mitochondrial dysfunction, nuclear dispersion and consequently cell death. We further demonstrated that FC could prevent biofilm formation of other Candida species and eradicate their pre-formed biofilms. An in vivo study demonstrated that FC prolonged the survival of C. albicans-infected Caenorhabditis elegans. Taken together, our study provides the basis for the application of FC to combat Candida infections.