以金色分枝杆菌为模式菌株筛选抗结核活性化合物可行性研究  

Study on the feasibility of searching anti-tuberculosis agents using Mycobacterium aureus

作　　者：蒙建州[1] 王潇[1] 关艳[1] 肖春玲[1] 刘忆霜[1] MENG Jian-zhou;WANG Xiao;GUAN Yan;XIAO Chun-ling;LIU Yi-shuang(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所重点室,北京100050

出　　处：《中国医药生物技术》2020年第4期386-391,共6页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81803412);中国医学科学院医学与健康科技创新工程(2016-I2M-1-013);中央高校基本科研业务费专项资金资助(3332019084)。

摘　　要：目的评估以金色分枝杆菌作为结核分枝杆菌模式菌株筛选抗结核抑制剂的可行性。方法以结核分枝杆菌标准菌株H37Rv建立细胞水平的抑制剂高通量筛选模型,对本单位化合物库部分样品进行筛选,获得具有抗结核活性的化合物;进一步比较模式菌株金色分枝杆菌、耻垢分枝杆菌、海分枝杆菌及谷氨酸棒状杆菌对具有较强抗结核活性样品的敏感性差异。结果利用基于结核分枝杆菌建立的全细胞筛选模型,从本单位化合物库的5万个样品中筛选得到67个最低抑菌浓度≤5μg/ml的化合物。对金色分枝杆菌、耻垢分枝杆菌、海分枝杆菌和谷氨酸棒状杆菌有抑制活性的样品分别有22个(32.84%)、10个(14.93%)、12个(17.91%)和6个(8.96%),其中抑菌活性与抗结核活性差异在4倍以内的样品分别有16个(72.73%)、5个(50%)、7个(58.33%)和3个(50%)。结论相对于其他3种模式菌株,金色分枝杆菌对本单位样品库化合物的敏感性与结核分枝杆菌的最为接近,以金色分枝杆菌为模式菌株开展抑制剂筛选研究更有可能获得具有抗结核活性的化合物。Objective We aim to evaluate the feasibility of screening for anti-tuberculosis agents using Mycobacterium aureus(Mau). Methods Firstly, a phenotypic high-throughput screening model was constructed using Mycobacterium tuberculosis(Mtb) H37 Rv to screen through sub-pool of our chemical-library for anti-tuberculosis agents, and their minimum inhibitory concentrations(MIC) to Mtb were tested via double broth dilution method. The best surrogate was determined by comparing sensitivities of Mau, Mycobacterium smegmatis(Msm), Mycobacterium marinum(Mma) and Corynebacterium glutamicum(Cgl) to compounds with potent anti-tuberculosis activities. Results Via the screening model, we obtained 67 compounds with potent anti-tuberculosis activities(MIC ≤ 5 μg/ml). Among these compounds, 22(32.84%), 10(14.93%), 12(17.91%) and 6(8.96%) displayed antibacterial activities to Mau, Msm, Mma and Cgl, respectively. Comparing with their anti-tuberculosis activities, 16(72.73%), 5(50%), 7(58.33%) and 3(50%) of these active compounds demonstrated < 4 times discrepancies in antibacterial potencies respectively. Conclusion Among these bacteria, Mau is the most suitable surrogate of Mtb used for searching anti-tuberculosis agents from our chemical library.

关 键 词：结核分枝杆菌 金色分枝杆菌 表型筛选 抗结核化合物 

分 类 号：R965.1[医药卫生—药理学]