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Netupitant Exhibits Potent Activity on Mycobacterium tuberculosis Persisters
Hassan E Eldesouky1, Richard M Jones1, Shabber Mohammed2
1Department of Microbiology, University of Washington, Seattle, Washington 98109, United States.
Abstract:
In Mycobacterium tuberculosis (Mtb), persisters are genotypically drug-sensitive bacteria that nonetheless survive antibiotic treatment. Persisters contribute to prolonged TB treatment duration and relapse risk, highlighting the need for new therapeutic strategies to effectively eliminate these tolerant subpopulations. In this study, we screened 2,336 FDA-approved compounds to identify agents that enhance the sterilizing activity of standard anti-TB drugs and prevent the regrowth of persisters. Netupitant (NTP), an FDA-approved antiemetic, emerged as a promising candidate. In combination with isoniazid (INH) and rifampicin (RIF), NTP eliminated viable Mtb cells, achieving a >6-log reduction in colony-forming units (CFUs), compared to the 2.5-log reduction observed with INH-RIF alone. NTP also demonstrated broad-spectrum efficacy, enhancing the activity of multiple TB drugs, including ethambutol, moxifloxacin, amikacin, and bedaquiline. Notably, NTP retained its potency under hypoxic and caseum-mimicking conditions, both of which are known to enrich for non-replicating, drug-tolerant cells. The mammalian target of NTP, the G protein-coupled receptor NK-1, is absent in bacteria, raising the possibility that the NTP target in bacteria is novel. To begin assessing this possibility, we performed transcriptomics and found that NTP significantly upregulates multiple oxidative stress response-associated genes, while downregulating pathways linked to protein synthesis, electron transport chain activities, and ATP synthesis. While further studies are required to decipher mechanisms of action and the resistance profile of NTP, and to assess its in vivo efficacy, these findings underscore its potential as a promising adjunct to existing TB therapies.
Insights
Netupitant (NTP) enhances standard tuberculosis drugs to kill persistent Mycobacterium tuberculosis (Mtb) cells, reducing bacterial load significantly and offering new hope for TB treatment.
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.
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