Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Tian Tan Xi Li, Chongwen district, Beijing, 100050, China.
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China.
Sci Rep. 2017 Jul 11;7(1):5093. doi: 10.1038/s41598-017-04108-7.
Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner. The compound did not inhibit human Akt1 or other serine/threonine kinases in M. tuberculosis except for the highly homologous PknA. IMB-YH-8 bound to PknB with a moderate affinity. Molecular docking revealed that IMB-YH-8 interacts with the catalytic domain of PknB. Observations of electron microscopy showed that IMB-YH-8 changed the morphology of H37Rv and disrupted the cell wall. The differential transcriptional response of M. tuberculosis to IMB-YH-8 revealed changes in SigH regulatory pathways modulated by PknB. Notably IMB-YH-8 not only potently inhibited drug-sensitive and multidrug-resistant clinical isolates but also exhibited a dose dependent inhibition of intracellular M. tuberculosis. Taken together, these in vitro data demonstrate that IMB-YH-8 is a novel inhibitor of PknB, which potently prevents growth of M. tuberculosis. It is as yet unclear whether inhibition of PknA contributes to the anti-tubercular action of IMB-YH-8.
蛋白激酶 B（PknB）是结核分枝杆菌丝氨酸/苏氨酸蛋白激酶之一，在维持分枝杆菌生长方面发挥着重要作用。在这里，我们鉴定并表征了一种新型小分子化合物，命名为 IMB-YH-8，它能抑制 PknB，是一种抗分枝杆菌的先导化合物。IMB-YH-8 能以剂量依赖的方式抑制 PknB 的自动磷酸化和 PknB 对 GarA 的磷酸化。该化合物不抑制人 Akt1 或结核分枝杆菌中的其他丝氨酸/苏氨酸激酶，除了高度同源的 PknA。IMB-YH-8 与 PknB 具有中等亲和力结合。分子对接表明 IMB-YH-8 与 PknB 的催化结构域相互作用。电子显微镜观察显示，IMB-YH-8 改变了 H37Rv 的形态并破坏了细胞壁。结核分枝杆菌对 IMB-YH-8 的差异转录反应显示，PknB 调节的 SigH 调控途径发生变化。值得注意的是，IMB-YH-8 不仅能强烈抑制药敏和耐多药的临床分离株，而且还能在一定程度上抑制细胞内结核分枝杆菌的生长。综上所述，这些体外数据表明，IMB-YH-8 是一种新型的 PknB 抑制剂，能有效抑制结核分枝杆菌的生长。目前尚不清楚抑制 PknA 是否有助于 IMB-YH-8 的抗结核作用。
Zotero 插件
