FIG 6.

Model depicting the therapeutic potential of AX20017. In response to Mtb infection, the host immune system contains the bacilli inside a granuloma. A granuloma is an organized and compact bunch of immune cells such as macrophages, multinucleated giant cells, dendritic cells, T cells, and B cells. Depending on the severity of the infection, granulomas can be of various kinds. The bacterium exploits this niche as its “safe haven” to survive and disseminate, leading to disease progression. The microaerophilic conditions found inside the granulomas drive cells of Mtb toward its nonreplicating antibiotic-tolerant persister phase. PknG helps Mtb adapt to hypoxic conditions by waning its metabolism. Deletion of pknG or its inhibition reduces Mtb’s ability to survive under in vivo latency-like conditions and attenuates its ability to thrive upon antibiotic stress. Hence, adjunct therapy with a PknG inhibitor could potentially suppress reactivation and lower the disease relapse rate and, hence, the transmission of the disease. The proof of principle for the interventions depicted in the schematic has been established with the help of various in vitro, ex vivo, and in vivo models of latency in this study.