Deletion of PknG abates reactivation of latent Mycobacterium tuberculosis in mice.

Eradication of tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has been a challenge due to its uncanny ability to survive dormantly inside the host granulomas for decades. Mtb rewires its metabolic and redox regulatory networks to survive in the hostile hypoxic and nutrient-limiting environment, facilitating the formation of the drug-tolerant persisters. Previously, we showed that Protein Kinase G (PknG), a virulence factor required for the lysosomal escape, aids in metabolic adaptation thereby promoting the survival of non-replicating mycobacterium. Here, we sought to investigate the therapeutic potential of PknG against latent mycobacterium. We show that inhibition of PknG by AX20017 reduces mycobacterial survival in vitro latency models such as hypoxia, persisters, and nutrient starvation. Targeting PknG enhances the bactericidal activity of the front-line anti-TB drugs in peritoneal macrophages. Deletion of pknG resulted in a five to fifteen-fold reduced survival of Mtb in chronically infected mice treated with anti-TB drugs. Importantly, in the Cornell mouse model of latent TB, the deletion of pknG drastically attenuated Mtb's ability to resuscitate post antibiotics treatment when compared with wild type and complemented strains. This is the first study to investigate the sterilizing activity of pknG deletion and inhibition for adjunct therapy against latent TB in a preclinical model. Collectively, the results suggest PknG may be a promising drug target for adjunct therapy to shorten the treatment duration and lower disease relapse.