Department of Dermatovenereology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Wuhou District, Chengdu, 610041, Sichuan Province, China.
State Key Laboratory of Oral Diseases, West China Stomatology Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
BMC Microbiol. 2020 Jun 16;20(1):165. doi: 10.1186/s12866-020-01850-3.
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.
白色念珠菌是最常见的机会性真菌病原体。由于现有抗真菌药物的局限性和耐药性的出现，开发具有新靶点的抗真菌药物是必要的。卤化喹啉醇的抗真菌活性得到了广泛的认可，但其确切机制仍不清楚。因此，本研究旨在探讨卤化喹啉醇抗白色念珠菌的可能机制。
在多种液体和固体培养基中，卤化喹啉醇可浓度依赖性地抑制菌丝形成。在不同的孵育期内，观察到浓度和时间依赖性的抗生物膜活性，无论是在数量上还是质量上。进一步的研究发现，卤化喹啉醇在高浓度下直接破坏细胞膜，并在低浓度下导致膜去极化。至于对离子稳态的影响，抗真菌作用可被外源添加金属离子所逆转。同时，在外源添加金属离子的培养基中，卤化喹啉醇的最小抑菌浓度增加，而在外源添加金属螯合剂的培养基中则降低。我们还发现，当真菌细胞用卤化喹啉醇处理时，细胞内可利用的亚铁离子水平降低。
这些结果表明，卤化喹啉醇可抑制白色念珠菌的酵母-菌丝过渡和生物膜形成。不同浓度的卤化喹啉醇对细胞膜的影响不同。同时，卤化喹啉醇可作为锌、铜和铁的金属螯合剂，干扰离子稳态，这与目前常用的抗真菌药物有很大不同。总之，尽管需要进一步研究以更好地了解确切的抗真菌机制，但卤化喹啉醇可以作为一种具有新靶点的有前途的新型抗真菌药物。
