A novel pH-responsive monomer inhibits Candida albicans via a dual antifungal mode of action.

The scarcity of the antifungal drug arsenal highlights an urgent need to develop alternative treatments for candidiasis caused by Candida albicans (C. albicans). As pH is closely associated with C. albicans infection, it could be an essential target in a novel approach for designing antifungal therapy. In this study, a novel intelligent antifungal monomer, dodecylmethylaminoethyl methacrylate (DMAEM), with a pH-responsive tertiary amine group and a methacrylate-derived CC double bond group is developed. It is uncovered that the two functional groups of DMAEM contribute to a dual mode of action. Under acidic pH, the tertiary amine of DMAEM protonates into a cationic fungicide, sharing similar structural and functional characteristics with quaternary ammonium salts, which exerts fungicidal activity by targeting the CHK1 two-component system in C. albicans. At neutral pH, the methacrylate-derived CC double bond group contributes to anti-virulence activity by blocking hyphal formation. In addition, it is also identified that DMAEM suppresses filamentation by altering the extracellular vesicles of C. albicans. These findings support that the novel intelligent pH-responsive monomer could be a therapeutic candidate for treating candidiasis.