The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy

A prolonged therapy regimen, primarily responsible for development of drug resistance by Mycobacterium tuberculosis (Mtb), the causative agent of human TB, obligates any new regimen to not only reduce treatment duration but also escape pathogen resistance mechanisms. With the aim of harnessing the host response in providing additional support to existing regimens (host directed therapy- HDT), we established the ability of a well-tolerated anti-depressant (sertraline - SRT) to modulate the pro-pathogenic type I IFN response of macrophages to Mtb infection. More importantly, while SRT alone could only arrest bacterial growth, it could effectively escalate the bactericidal activities of Isoniazid (H) and Rifampicin (R) in macrophages. This strengthening of antibiotic potencies by SRT was more evident in conditions of ineffective control by these frontline TB drugs: against HR tolerant strains or dormant Mtb. SRT, could significantly combine with standard TB drugs to enhance early pathogen clearance from tissues of mice infected with either drug sensitive/ tolerant strains of Mtb. Further, we demonstrate an enhanced protection of the highly susceptible C3HeB/FeJ mice in an acute model of TB infection with the combination therapy signifying the use of SRT as a potent adjunct to standard TB therapeutic regimens against bacterial populations of diverse physiology. This study advocates a novel host directed adjunct therapy regimen for TB with an FDA approved and well tolerated anti-depressant to achieve quicker and better control of infection.