药学学报, 2022, 57(4): 1024-1030
引用本文:
刘伟, 王苗苗, 韩研春, 倪萍, 温芝潼, 袁林, 王胜正. 5碘代杀结核菌素的抗真菌及作用机制研究[J]. 药学学报, 2022, 57(4): 1024-1030.
LIU Wei, WANG Miao-miao, HAN Yan-chun, NI Ping, WEN Zhi-tong, YUAN Lin, WANG Sheng-zheng. Activities of 5-iodotubercidin against pathogenic fungi and its mode of actions[J]. Acta Pharmaceutica Sinica, 2022, 57(4): 1024-1030.

5碘代杀结核菌素的抗真菌及作用机制研究
刘伟1, 王苗苗1, 韩研春1, 倪萍1, 温芝潼1, 袁林1, 王胜正2*
1. 陕西科技大学药学系, 陕西 西安 710021;
2. 中国人民解放军空军军医大学药学院, 陕西 西安 710027
摘要:
侵袭性真菌感染的高发生率和死亡率使其成为临床的一大棘手难题。真菌耐药性的出现进一步增加其治疗难度。因此,开发新型抗真菌药物是解决该难题的策略之一。蛋白激酶类抑制剂在肿瘤、糖尿病和风湿病等领域被广泛研究,但在抗真菌领域研究较少。本研究经前期筛选100个结构多样的蛋白激酶类小分子抑制剂的抗真菌活性,发现12个化合物表现不同程度的抗真菌活性,其中5碘代杀结核菌素(5-Itu)的抗真菌活性较优(最小抑菌浓度范围为2~4 μg·mL-1)。同时,体外活性评价实验发现该化合物还具有良好的杀菌、抗生物被膜和抑制菌丝形成的活性。作用机制研究显示,5-Itu可改变细胞膜甾醇成分和超微结构,增加细胞膜通透性,诱导细胞凋亡。因此对其进一步研究,有望发现新型的抗真菌先导化合物。
关键词:    5碘代杀结核菌素      抗真菌      抗生物被膜      腺苷激酶抑制剂      作用机制     
Activities of 5-iodotubercidin against pathogenic fungi and its mode of actions
LIU Wei1, WANG Miao-miao1, HAN Yan-chun1, NI Ping1, WEN Zhi-tong1, YUAN Lin1, WANG Sheng-zheng2*
1. Faculty of Pharmacy, Shaanxi University of Science and Technology, Xi'an 710021, China;
2. School of Pharmacy, Fourth Military Medical University, Xi'an 710027, China
Abstract:
Invasive fungal infections are a tricky problem with high morbidity and mortality. The emerging of drug resistance worsens this problem. Therefore, developing novel antifungal agents is an urgent need to break these hurdles. Although protein kinase inhibitors have been extensively investigated in various fields such as cancer, diabetes, rheumatosis and so on, they are less explored in fungal infection. Previously, we found 12 protein kinase inhibitors with different antifungal activities, among them 5-iodotubercidin (5-Itu) was found to be the most potent antifungal agent with minimal inhibitory concentrations ranging from 2 to 4 μg·mL-1. Moreover, 5-Itu displayed potent fungicidal effect, inhibition of hyphal formation and anti-biofilm activity. The mechanistic studies indicated that 5-Itu changed membrane sterol compositions and ultrastructures, increased the cell membrane permeability and induced apoptosis. Therefore, it needs to further study 5-Itu for the discovery of promising antifungal lead compounds.
Key words:    5-iodotubercidin    antifungal    anti-biofilm    adenosine kinase inhibitor    mode of action   
收稿日期: 2021-10-14
DOI: 10.16438/j.0513-4870.2021-1484
基金项目: 国家自然科学基金资助项目(81701981);陕西重点研究计划一般项目(2020SF-205);大学生创新创业训练项目(201910708013).
通讯作者: 王胜正,Tel/Fax:86-29-84776815,E-mail:wangshengzheng001@163.com
Email: wangshengzheng001@163.com
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