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. 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. 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.

中文翻译：

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氯喹醇对白色念珠菌的形态发生，细胞膜和离子稳态的影响。

白色念珠菌是最普遍的机会性真菌病原体。开发具有新型靶标的抗真菌药对于限制目前的抗真菌药和产生耐药性是必要的。氯喹醇的抗真菌活性已被广泛接受，但其确切机理尚不清楚。因此，在本研究中，我们旨在寻找氯碘喹抗白念珠菌的可能机制。Clioquinol可以在多种液体和固体介质中以浓度依赖的方式抑制菌丝的形成。在不同的潜伏期，定量和定性地观察到浓度和时间依赖性的抗生物膜活性。进一步的研究发现，氯喹啉在高浓度下会直接破坏细胞膜，在低浓度下会引起膜去极化。至于对离子稳态的影响，可通过外源添加金属离子逆转氯喹诺的抗真菌作用。同时，在添加外源金属离子的培养基中，氯喹喹的最低抑菌浓度增加，而在添加外源金属螯合剂的培养基中，最小抑制浓度降低。我们还发现，用氯喹醇处理真菌细胞后，细胞中不稳定的亚铁水平降低。这些结果表明，氯喹醇可以抑制白色念珠菌的酵母菌丝过渡和生物膜形成。对细胞膜的作用因氯喹醇的不同浓度而异。同时，作为对锌，铜和铁的金属螯合剂，氯喹诺酮可能会干扰离子稳态，这与目前的常用抗真菌剂大不相同。总而言之，