Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Mycobacterium tuberculosis (M. tuberculosis) utilizes Protein Kinase G (PknG) to evade host immune responses.
• PknG suppresses phagosome-lysosome fusion, enhancing mycobacterial survival within macrophages.
• Targeting PknG is a promising strategy for developing novel anti-mycobacterial agents.

Purpose of the Study:

• To identify novel inhibitors of PknG.
• To evaluate the anti-mycobacterial potential of identified PknG inhibitors.

Main Methods:

• A luciferase-based PknG kinase assay was employed for inhibitor screening.
• Mycobacterial survival assays in human macrophages were conducted.
• Cytotoxicity assays were performed to assess compound safety.

Main Results:

• Four compounds (AZD7762, R406, R406-free base, CYC116) demonstrated PknG inhibitory activity.
• AZD7762, R406, and R406-free base promoted mycobacterial transfer to lysosomes.
• R406 and R406-free base exhibited bactericidal activity against M. bovis BCG in macrophages without cytotoxicity.

Conclusions:

• The identified PknG inhibitors show potential as anti-mycobacterial agents.
• R406 and its free base are particularly promising due to their bactericidal and non-cytotoxic properties.
• Further development of these PknG inhibitors could lead to new treatments for tuberculosis.