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NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G

Kidwai, Saqib and Bouzeyen, Rania and Chakraborti, Sohini and Khare, Neha and Das, Sumana and Gosain, Tannu Priya and Behura, Assirbad and Meena, Chhuttan Lal and Dhiman, Rohan and Essafi, Makram and Bajaj, Avinash and Saini, Deepak Kumar and Srinivasan, Narayanaswamy and Mahajan, Dinesh and Singh, Ramandeep (2019) NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G. In: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 63 (9).

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Official URL: https://dx.doi.org/10.1128/AAC.00996-19

Abstract

Tuberculosis (TB) is a global health concern, and this situation has further worsened due to the emergence of drug-resistant strains and the failure of BCG vaccine to impart protection. There is an imperative need to develop highly sensitive, specific diagnostic tools, novel therapeutics, and vaccines for the eradication of TB. In the present study, a chemical screen of a pharmacologically active compound library was performed to identify antimycobacterial compounds. The phenotypic screen identified a few novel small-molecule inhibitors, including NU-6027, a known CDK-2 inhibitor. We demonstrate that NU-6027 inhibits Mycobacterium bovis BCG growth in vitro and also displayed cross-reactivity with Mycobacterium tuberculosis protein kinase D (PknD) and protein kinase G (PknG). Comparative structural and sequence analysis along with docking simulation suggest that the unique binding site stereochemistry of PknG and PknD accommodates NU-6027 more favorably than other M. tuberculosis Ser/Thr protein kinases. Further, we also show that NU-6027 treatment induces the expression of proapoptotic genes in macrophages. Finally, we demonstrate that NU-6027 inhibits M. tuberculosis growth in both macrophage and mouse tissues. Taken together, these results indicate that NU-6027 can be optimized further for the development of antimycobacterial agents.

Item Type: Journal Article
Additional Information: copyright for this article belongs to AMER SOC MICROBIOLOGY
Keywords: Mycobacterium tuberculosis; NU-6027; serine threonine protein kinases; apoptosis
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Depositing User: Id for Latest eprints
Date Deposited: 05 Nov 2019 11:23
Last Modified: 05 Nov 2019 11:23
URI: http://eprints.iisc.ac.in/id/eprint/63642

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