A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity

作者：Xu, Jian; Wang, Ju-xian; Zhou, Jin-ming; Xu, Chang-liang; Huang, Bin; Xing, Yun; Wang, Bin; Luo, Rui; Wang, Yu-cheng; You, Xue-fu; Lu, Yu^*; Yu, Li-yan

来源：Scientific Reports, 2017, 7(1): 5093.

DOI：10.1038/s41598-017-04108-7

• MYCOBACTERIUM-TUBERCULOSIS
• PKNB
• GROWTH
• IDENTIFICATION
• EXPRESSION
• GENES

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.

• 出版日期2017-7-11
• 单位北京协和医学院; 中国医学科学院北京协和医院; 北京市结核病胸部肿瘤研究所; 河北医科大学; 首都医科大学; 北京老年医院