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

Autor: Narayanaswamy Srinivasan, Avinash Bajaj, Makram Essafi, Ramandeep Singh, Tannu Priya Gosain, Dinesh Mahajan, Rania Bouzeyen, Neha Khare, Saqib Kidwai, Rohan Dhiman, Sohini Chakraborti, Assirbad Behura, Deepak Kumar Saini, Chhuttan Lal Meena, Sumana Das
Rok vydání: 2019
Předmět:
Tuberculosis
medicine.drug_class
Antitubercular Agents
Serine threonine protein kinase
Microbial Sensitivity Tests
Protein Serine-Threonine Kinases
Antimycobacterial
Protein Structure
Secondary
Microbiology
Mycobacterium tuberculosis
Small Molecule Libraries
03 medical and health sciences
Bacterial Proteins
medicine
Pharmacology (medical)
Protein Interaction Domains and Motifs
Protein Kinase Inhibitors
Mechanisms of Action: Physiological Effects
Protein Kinase C
030304 developmental biology
Pharmacology
0303 health sciences
Mycobacterium bovis
Binding Sites
biology
030306 microbiology
Kinase
Macrophages
medicine.disease
biology.organism_classification
High-Throughput Screening Assays
Molecular Docking Simulation
Infectious Diseases
Pyrimidines
Gene Expression Regulation
Host-Pathogen Interactions
Apoptosis Regulatory Proteins
BCG vaccine
cGMP-dependent protein kinase
Nitroso Compounds
Protein Binding
Zdroj: Antimicrobial agents and chemotherapy. 63(9)
ISSN: 1098-6596
Popis: 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.
Databáze: OpenAIRE
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