Chemical biology to target TB persisters

Tuberculosis (TB) remains a global health crisis, claiming over a million lives annually. A major barrier to treatment success is the persistence of drug-tolerant Mycobacterium tuberculosis (Mtb) cells, which evade standard antibiotics, prolong therapy, and contribute to relapse. Addressing this challenge, we developed a drug screening assay and identified netupitant (NTP), an FDA-approved antiemetic, as a potent anti-persister agent. NTP exerted a bacteriostatic activity on its own, however, in combination with isoniazid (INH) and rifampicin (RIF), NTP eliminated viable Mtb cells within 7 days, achieving a >6-log reduction in colony-forming units (CFUs) compared to the 2.5-log reduction observed with INH-RIF alone. Furthermore, NTP enhanced the activity of multiple TB drugs, including ethambutol, moxifloxacin, amikacin, and bedaquiline, demonstrating broad-spectrum efficacy. Crucially, NTP retained its potency under hypoxic and caseum-mimicking conditions, which are known to promote non-replicating, drug-tolerant Mtb populations. These findings position NTP as a promising candidate for enhancing TB treatment efficacy, potentially shortening therapy duration and reducing relapse risk.