In vitro and in vivo efficacy of PI3Kγ inhibitor AS605240 in controlling mycobacterial infections

Inhibition of PI3Kγ is an attractive therapeutic target for the development of novel host-directed modulating strategies for the treatment of infectious diseases. This work investigated the antimicrobial potential of AS605240, a selective inhibitor of PI3Kγ, in pre-clinical models of mycobacterial infections. Of note, we observed that treatment with AS605240 effectively reduced both intracellular M. smegmatis and M. tuberculosis counts in RAW 264.7 cells. Moreover, treatment of M. tuberculosis-infected cells with AS605240 increased TNF-α and decreased IL-1β levels compared to the infected group. Importantly, we found that AS605240 is bacteriostatic in the lungs and bactericidal in spleens from M. tuberculosis-infected mice. Our data provide novel evidence on the relevance of PI3Kγ as a novel molecular target for new anti-tubercular drugs.