Sertraline Enhances Bacterial Control without Adversely Affecting the Pharmacodynamic–Pharmacokinetic Properties of Frontline Tuberculosis Drugs

Host-directed therapies (HDTs) are gaining importance as innovative intervention strategies for shortening the treatment durations of tuberculosis (TB), a major public health burden. The combination of TB drugs and sertraline (SRT), an FDA-approved antidepressant, has shown promise in reducing the treatment duration and advancing tissue recovery in murine models. This study evaluates sertraline as an adjunct in the guinea pig model of infection that mimics human variability and its impact on TB drug pharmacokinetics (PK). Random-bred guinea pigs infected with Mycobacterium tuberculosis (Mtb) were treated with frontline TB drugs, with or without sertraline, and the effect of the combination on bacterial loads and lung histopathology was assessed to evaluate disease severity. In addition, the pharmacokinetic and pharmacodynamic (PD) interactions following coadministration of the standard TB drugs with SRT were assessed at multiple time points over 24 h in rat tissues. The SRT and anti-TB drug combination significantly reduced bacterial loads and tissue damage in guinea pig tissues compared with standard therapy alone. Pharmacokinetic analyses in rats revealed that SRT does not adversely affect TB drug distribution or clearance, although a transient but insignificant enrichment of drug levels was observed between 3 and 6 h in various tissues. SRT enhanced TB treatment without compromising drug pharmacokinetics, suggesting a safe and effective adjunct to the current regimen. These findings, coupled with the existing FDA approval and safety profile for clinical use of SRT, highlight its potential as an adjunct to improve TB therapy outcomes.