Sci Rep. 2017 Jul 11;7(1):5093. doi: 10.1038/s41598-017-04108-7.

Xu J1,2, Wang JX1, Zhou JM1, Xu CL1, Huang B1, Xing Y1, Wang B2, Luo R1, Wang YC1, You XF1, Lu Y3, Yu LY4.

Author information

1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Tian Tan Xi Li, Chongwen district, Beijing, 100050, China.

2 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China.

3 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China. luyu4876@hotmail.com.

4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Tian Tan Xi Li, Chongwen district, Beijing, 100050, China. yly@cpcc.ac.cn.

Abstract

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.

PMID:28698545   PMCID:PMC5506005  DOI:10.1038/s41598-017-04108-7

https://www.ncbi.nlm.nih.gov/pubmed/?term=A+novel+protein+kinase+inhibitor+IMB-YH-8+with+anti-tuberculosis+activity