The effects of clioquinol in morphogenesis, cell membrane and ion homeostasis in Candida albicans

Background: Candida albicans is the most prevalent opportunistic Fungal pathogen. Development of antifungals with novel targets is necessary for limitations of current Antifungal agents and the emergence of drug resistance. The Antifungal activity of clioquinol was widely accepted while the precise mechanism was poorly understood. Hence, we aimed to seek for the possible mechanism of clioquinol against Candida albicans in the present study.

Results: Clioquinol could inhibit hyphae formation in a concentration-dependent manner in multiple liquid and solid media. The concentration and time-dependent anti-biofilm activities were observed in different incubation periods quantitatively and qualitatively. Further investigation found that clioquinol disrupted cell membrane directly in high concentration and induced depolarization of the membrane in low concentration. As for the influence on ion homeostasis, the Antifungal effects of clioquinol could be reversed by exogenous addition of metal ions. Meanwhile, the minimum inhibitory concentration of clioquinol was increased in media supplemented with exogenous metal ions and decreased in media supplemented with exogenous metal chelators. We also found that the cellular labile ferrous iron level decreased when Fungal cells were treated with clioquinol.

Conclusion: These results indicated that clioquinol could inhibit yeast-hyphae transition and biofilm formation in Candida albicans. The effect on the cell membrane was different depending on different concentrations of clioquinol. Meanwhile, clioquinol could interfere with ion homeostasis as metal chelators for zinc, copper and iron, which was quite different with current common Antifungal agents. All in all, clioquinol can be a new promising Antifungal agent with novel target though more studies are needed to better understand the precise Antifungal mechanism.