Netupitant Exhibits Potent Activity on Mycobacterium tuberculosis Persisters

Area of Science:

• Microbiology and Infectious Diseases
• Drug Discovery and Pharmacology

Background:

• Persistent Mycobacterium tuberculosis (Mtb) cells are drug-tolerant and contribute to prolonged treatment and relapse in tuberculosis (TB).
• Novel therapeutic strategies are needed to eliminate these persistent subpopulations effectively.

Purpose of the Study:

• To screen FDA-approved compounds for their ability to enhance the sterilizing activity of standard anti-TB drugs against Mtb persisters.
• To identify novel agents that can prevent the regrowth of Mtb persisters.

Main Methods:

• Screened 2,336 FDA-approved compounds for synergistic activity with anti-TB drugs.
• Evaluated the efficacy of promising candidates, like Netupitant (NTP), in combination with isoniazid (INH) and rifampicin (RIF) against Mtb persisters.
• Assessed NTP's activity under hypoxic and caseum-mimicking conditions using transcriptomics to explore its mechanism of action.

Main Results:

• Netupitant (NTP) significantly enhanced the sterilizing activity of INH-RIF, achieving a >6-log reduction in colony-forming units (CFUs) compared to 2.5-log with INH-RIF alone.
• NTP demonstrated broad-spectrum efficacy, boosting the activity of other TB drugs including ethambutol, moxifloxacin, amikacin, and bedaquiline.
• NTP retained potency under conditions that enrich for drug-tolerant Mtb and modulated oxidative stress response and protein synthesis pathways.

Conclusions:

• Netupitant (NTP) is a promising adjunct therapy candidate for tuberculosis, effectively eliminating persistent Mtb cells when combined with standard drugs.
• NTP's novel bacterial target, distinct from its mammalian NK-1 receptor, warrants further investigation into its mechanism of action and resistance profile.
• Further in vivo studies are necessary to confirm NTP's efficacy and potential as a novel anti-TB agent.