Lack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System.
Lack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System.
复制标题
结核分枝杆菌 FAS-II 系统抑制剂的表型筛选缺乏特异性。
DOI：
10.1128/aac.01914-20
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发表时间：
2020
影响因子：
4.9
通讯作者：
Jackson,Mary
中科院分区：
文献类型：
--
作者：
Grzegorzewicz,AnnaE;Lelièvre,Joël;Esquivias,Jorge;Angala,Bhanupriya;Liu,Jiuyu;Lee,RichardE;McNeil,MichaelR;Jackson,Mary
通过对结核分枝杆菌Fas-II脱水酶抑制剂HADAB的表型筛选，鉴定出GSK3011724A，这是一种先前报道的抑制Fas-II缩合步骤的化合物。基于全细胞和无细胞的分析证实，尽管GSK3011724A和HADAB抑制剂之间存在交叉耐药性，但GSK3011724A对脱水酶缺乏活性。抗性机制的本质暗示了Fas-II相互作用体的改变，减少了GSK3011724A对Kasa的访问。
Phenotypic screening of inhibitors of the essential Mycobacterium tuberculosis FAS-II dehydratase HadAB led to the identification of GSK3011724A, a compound previously reported to inhibit the condensation step of FAS-II. Whole-cell-based and cell-free assays confirmed the lack of activity of GSK3011724A against the dehydratase despite evidence of cross-resistance between GSK3011724A and HadAB inhibitors. The nature of the resistance mechanisms is suggestive of alterations in the FAS-II interactome reducing access of GSK3011724A to KasA.