Synergy and mechanism of tedizolid in combination with fluconazole against resistant Candida albicans

Objective To evaluate the synergistic antifungal activity of tedizolid (TDZ) in combination with fluconazole (FLC) against Candida albicans, including drug-resistant strains, and to elucidate the underlying mechanisms of synergistic action.Materials and methods The antifungal activity of TDZ and FLC combination was assessed against planktonic cells and preformed biofilms of C. albicans in vitro. To assess in vivo antimicrobial effect, a Galleria mellonella larval infection model was employed. Mechanistic investigations included reactive oxygen species (ROS) detection, yeast-to-hypha transition assays, metacaspase activity analysis, intracellular Ca2+ measurement, and drug uptake and efflux assays.Results Synergistic antifungal effects were observed when TDZ was used in conjunction with FLC against both planktonic cells and preformed biofilms of C. albicans, particularly drug-resistant strains. In vivo, combination therapy significantly improved survival rates and reduced tissue damage in infected G. mellonella. Mechanistic studies revealed that synergistic inhibition was associated with ROS accumulation, impaired filamentous development, metacaspase activation, and disruption of Ca2+ homeostasis, but was independent of drug uptake and efflux pathways.Conclusions The TDZ and FLC combination demonstrates the significant cooperative antimycotic potential against resistant C. albicans, providing a foundation for developing novel therapeutic strategies against resistant candidiasis and offering valuable insights into new antifungal agent development.