去乙酰化酶抑制剂AK-1对氟康唑体外抑制白念珠菌生长的影响

doi:10.35541/cjd.20240668

中华皮肤科杂志 ›› 2025, Vol. 58 ›› Issue (12): 1141-1147.doi: 10.35541/cjd.20240668

• 论著·真菌感染性皮肤病 • 上一篇下一篇

去乙酰化酶抑制剂AK-1对氟康唑体外抑制白念珠菌生长的影响

周晓伟^1，2 梅嬛¹ 刘维达^1，2 李筱芳^1，2

¹中国医学科学院、北京协和医学院皮肤病医院皮肤病研究所真菌科，南京 210042；²江苏省皮肤医学重点实验室，南京 210042

收稿日期:2024-12-05 修回日期:2025-10-21 发布日期:2025-12-04
通讯作者: 李筱芳 E-mail:Lxf3568@163.com
基金资助:
国家自然科学基金（82073455，82273546，81903229）；国家重点研发计划（2022YFC2504804）；江苏省科技能力提升工程江苏医学重点实验室（ZDXYS202204）

Effect of the deacetylase inhibitor AK-1 on the in vitro activity of fluconazole against Candida albicans

Zhou Xiaowei^1,2, Mei Huan¹, Liu Weida^1,2, Li Xiaofang^1,2

¹Department of Medical Mycology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences ＆ Peking Union Medical College, Nanjing 210042, China; ²Jiangsu Provincial Key Laboratory of Dermatology, Nanjing 210042, China

Received:2024-12-05 Revised:2025-10-21 Published:2025-12-04
Contact: Li Xiaofang E-mail:Lxf3568@163.com
Supported by:
National Natural Science Foundation of China （82073455, 82273546, 81903229）; National Key Research and Development Program of China （2022YFC2504804）; Jiangsu Provincial Medical Key Laboratory, Jiangsu Province Capability Improvement Project through Science, Technology, and Education （ZDXYS202204）

摘要/Abstract

摘要： 【摘要】目的探讨去乙酰化酶抑制剂AK-1对氟康唑（FCZ）抑制白念珠菌的影响。方法配制含0.062 5 ~ 32 μg/ml FCZ药液的1640培养基平板，接种白念珠菌，24 h后观察菌株生长。采用75 μmol/L AK-1（+/-）、溶剂DMSO（+/-）与低浓度（0.062 5、0.125 μg/ml）FCZ（+/-）作用24 h，观察对白念珠菌生长的抑制作用；采用Western印迹检测AK-1与FCZ处理对白念珠菌乙酰化修饰、巴豆酰化修饰的影响，以空白组（AK-1-/DMSO-/FCZ-）相对水平为1得到各组归一化的相对乙酰化修饰和巴豆酰化修饰水平。多组间比较采用单因素方差分析，组间多重比较采用LSD-t检验。结果 0.125 ~ 32 μg/ml FCZ均可明显抑制白念珠菌生长。DMSO与FCZ共处理（AK-1-/DMSO+/FCZ+组）对白念珠菌生长的抑制程度较单独FCZ 处理（AK-1-/DMSO-/FCZ+处理组）明显，加入AK-1共处理时（AK-1+/DMSO+/FCZ+组）可逆转DMSO与FCZ共处理对白念珠菌生长的抑制作用。0.062 5 μg/ml FCZ单独处理时（AK-1-/DMSO-/FCZ+组）乙酰化修饰水平（0.766 ± 0.055）、巴豆酰化修饰水平（0.856 ± 0.032）均低于空白组（均P < 0.05）；DMSO和FCZ（AK-1-/DMSO+/FCZ+组）共同处理时，乙酰化修饰水平（0.501 ± 0.073）、巴豆酰化修饰水平（0.723 ± 0.044）较FCZ单独处理时更低（均P < 0.05）；而加入AK-1共处理后（AK-1+/DMSO+/FCZ+组）乙酰化修饰水平（0.846 ± 0.014）、巴豆酰化修饰水平（1.325 ± 0.119）较DMSO和FCZ（AK-1-/DMSO+/FCZ+组）共同处理时更高，但加入AK-1后乙酰化修饰水平仍低于空白组，而巴豆酰化修饰水平高于空白组（均P < 0.05）。结论去乙酰化酶抑制剂AK-1可能通过调控乙酰化修饰和巴豆酰化修饰从而逆转FCZ对白念珠菌的抑制作用。

关键词: 白念珠菌, 氟康唑, 抗衰老酶2抑制剂, AK-1, 乙酰化修饰, 巴豆酰化修饰

Abstract: 【Abstract】 Objective To investigate the effect of the deacetylase inhibitor AK-1 on the antifungal activity of fluconazole （FCZ） against Candida albicans （C. albicans）. Methods RPMI-1640 media containing FCZ at different concentrations of 0.0625 - 32 μg/ml were prepared. C. albicans strains were inoculated onto the medium plates, and the growth was observed after 24 hours. The inhibitory effects on fungal growth were assessed after 24-hour treatment with or without 75 μmol/L AK-1 （+/-）, solvent dimethyl sulfoxide （DMSO）（+/-）, and low concentrations of FCZ （0.0625, 0.125 μg/ml）（+/-）. Western blot analysis was performed to evaluate the effects of AK-1 and FCZ on acetylation and crotonylation modifications in C. albicans, and normalized relative levels of acetylation and crotonylation modifications were calculated with the values of the blank group （AK-1-/DMSO-/FCZ- group） set as the baseline value of 1. One-way analysis of variance was used for comparisons among multiple groups, and the least significant difference-t test for multiple comparisons. Results FCZ at concentrations of 0.125 - 32 μg/ml markedly inhibited the growth of C. albicans. Co-treatment with DMSO and FCZ （AK-1-/DMSO+/FCZ+ group） resulted in stronger inhibition of fungal growth compared with the FCZ treatment alone （AK-1-/DMSO-/FCZ+ group）. However, the addition of AK-1 （AK-1+/DMSO+/FCZ+ group） reversed the inhibitory effect of DMSO and FCZ on fungal growth. Further experiments demonstrated that both acetylation （0.766 ± 0.055） and crotonylation levels （0.856 ± 0.032） were significantly reduced （both P < 0.05） in the AK-1-/DMSO-/FCZ+ group （0.0625 μg/ml FCZ treatment alone） compared with the blank group; co-treatment with DMSO and FCZ （AK-1-/DMSO+/FCZ+ group） further decreased acetylation （0.501 ± 0.073） and crotonylation levels （0.723 ± 0.044） compared with FCZ treatment alone （both P < 0.05）; the AK-1+/DMSO+/FCZ+ group showed increased acetylation （0.846 ± 0.014） and crotonylation levels （1.325 ± 0.119） compared with the AK-1-/DMSO+/FCZ+ group, while exhibited significantly lower acetylation levels but significantly higher crotonylation levels than the blank group （both P < 0.05）. Conclusion The deacetylase inhibitor AK-1 may reverse the inhibitory effect of FCZ on C. albicans by regulating acetylation and crotonylation modifications.

Key words: Candida albicans, Fluconazole, Sirtuin 2 inhibitor, AK-1, Acetylation, Crotonylation

周晓伟, 梅嬛刘维达, 李筱芳, . 去乙酰化酶抑制剂AK-1对氟康唑体外抑制白念珠菌生长的影响[J]. 中华皮肤科杂志, 2025,58(12):1141-1147. doi:10.35541/cjd.20240668

Zhou Xiaowei, Mei Huan, Liu Weida, Li Xiaofang, . Effect of the deacetylase inhibitor AK-1 on the in vitro activity of fluconazole against Candida albicans[J]. Chinese Journal of Dermatology, 2025, 58(12): 1141-1147.doi:10.35541/cjd.20240668

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去乙酰化酶抑制剂AK-1对氟康唑体外抑制白念珠菌生长的影响

Effect of the deacetylase inhibitor AK-1 on the in vitro activity of fluconazole against Candida albicans

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