Clioquinol influences cell membrane, attenuates virulence factors, induces apoptosis to inhibit Candida albicans growth

Aim: To investigate the antifungal mechanism of clioquinol and indicate that clioquinol has potential as a novel therapeutic antifungal agent. Materials & methods: Analyze differentially expressed genes of Candida albicans treated with clioquinol using RNA-sequencing. The effects on cell wall and membrane features, virulence factors, apoptosis-induced cell death were also investigated. Results: The differentially expressed genes of C. albicans after treated with clioquinol focused on cell wall and membrane synthesis, antioxidant system and energy metabolism. Clioquinol did not change cell wall components levels while it decreased squalene epoxidase activity to influence the ergosterol biosynthesis in cell membrane. It also decreased cellular surface hydrophobicity and induced β-glucan unmasking to attenuate virulence factors. Meanwhile, clioquinol influenced enzyme activities involved in antioxidant system, citrate cycle, oxidative phosphorylation and decreased the ATP levels. Clioquinol induced apoptosis in C. albicans to exert its fungicidal activity. It induced reactive oxygen species and calcium ion elevation, leading to loss of mitochondrial membrane potential, cytochrome C release, metacaspase activation, thereby triggering apoptosis. Conclusion: Clioquinol exerted anti-C. albicans activity through influencing cell membrane, attenuating virulence factors and inducing apoptosis. Clioquinol changed gene expressions involved in cell wall and membrane synthesis, antioxidant system and energy metabolism in Candida albicans. Clioquinol influenced the ergosterol biosynthesis in cell membrane and attenuated virulence factors in C. albicans. Clioquinol influenced gene expressions and enzyme activities involved in antioxidant system, citrate cycle and oxidative phosphorylation. Meantime it decreased the ATP levels. Clioquinol induce apoptosis in C. albicans through influencing reactive oxygen species and calcium ion levels. The study provided more evidences for the antifungal mechanism of clioquinol. Clioquinol emerges as promising candidates for the development of novel antifungal therapies.