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

  • Sci Rep. 2017 Jul 11;7(1):5093. doi: 10.1038/s41598-017-04108-7.
Jian Xu  1  2 ,  Ju-Xian Wang  1 ,  Jin-Ming Zhou  1 ,  Chang-Liang Xu  1 ,  Bin Huang  1 ,  Yun Xing  1 ,  Bin Wang  2 ,  Rui Luo  1 ,  Yu-Cheng Wang  1 ,  Xue-Fu You  1 ,  Yu Lu  3 ,  Li-Yan Yu  4
Affiliations
  • 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. [email protected].
  • 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. [email protected].
PMID: 28698545 DOI: 10.1038/s41598-017-04108-7
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.

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