Advancing host-directed therapy for tuberculosis/MDR-TB

Aim and Objective: Previous studies reported the implications of host-immune cell signalling pathways contributing towards survival of mycobacteria. Among the few, abrogation of PI3K-AKT-mTOR pathway has been shown to impact bacterial viability in macrophages. However, the intricate molecular mechanisms associated with such outcome at the juncture of host-pathogen interaction remain elusive. Methods: We have used novel AKT inhibitor against MTB infected macrophage and tested its survivability and its molecular mechanism of killing inside macrophage. Result: In the present work mouse peritoneal macrophages infected with pathogenic strain of M.tb (H37Rv) exhibited increased phosphorylation of AKT. Interestingly, suppression of AKT activity by a novel small molecule inhibitor during mycobacterial infection promoted phagolysosome fusion, apoptosis and autophagy, altogether contributing towards reduction in bacterial count in vitro. At the molecular level, we noticed that, small molecule inhibitor to AKT treatment deciphered the requirement of phosphorylation of AS160, Bad and mTOR by phosphorylated AKT in infected macrophages. Additionally, inhibition of phosphorylated AKT hampered nuclear translocation of NF-kB resulting in decreased cytokine expression. Conclusion: Taken together, our inhibitor can be utilized as an adjunctive therapy, as it shows high efficacy in decreasing bacterial count in combination with standard drugs to TB and also prevent the development of antibiotic resistance as host pathways are being targeted.