{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:17:28Z","timestamp":1768519048564,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,30]]},"group-title":"Microbiology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  In\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (Mtb), persisters are genotypically drug-sensitive bacteria that nonetheless survive antibiotic treatment. Persisters represent a significant challenge to shortening TB treatment and preventing relapse, underscoring the need for new therapeutic strategies. 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 with bacteriostatic activity on its own. However, in combination with isoniazid (INH) and rifampicin (RIF), NTP eliminated viable Mtb cells within 7 days, achieving a &gt;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. Interestingly, under hypoxic conditions, NTP demonstrated strong tuberculocidal activity, achieving an approximate 4-log CFU reduction, whereas high-dose INH-RIF was ineffective. Transcriptomic analysis revealed that NTP primarily disrupts cellular bioenergetics, with significant downregulation observed in activities associated with the electron transport chain, oxidative phosphorylation, NADH-ubiquinone oxidoreductase, succinate dehydrogenase, and ATP synthesis. While further studies are required to decipher the mechanism of action and resistance profile of NTP, and to assess its\n                  <jats:italic>in vivo<\/jats:italic>\n                  efficacy, these findings underscore its potential as a promising adjunct to existing TB therapies.\n                <\/jats:p>","DOI":"10.1101\/2024.10.30.620736","type":"posted-content","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T23:30:13Z","timestamp":1730331013000},"source":"Crossref","is-referenced-by-count":1,"title":["Netupitant Exhibits Potent Activity on\n                  <i>Mycobacterium tuberculosis<\/i>\n                  Persisters"],"prefix":"10.64898","author":[{"given":"Hassan E.","family":"Eldesouky","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Gleason","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shabber","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enming","family":"Xing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pui-Kai","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Sherman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024110400001175000_2024.10.30.620736v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00731-y"},{"key":"2024110400001175000_2024.10.30.620736v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.01858"},{"key":"2024110400001175000_2024.10.30.620736v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-016-2171-1"},{"key":"2024110400001175000_2024.10.30.620736v1.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030384"},{"key":"2024110400001175000_2024.10.30.620736v1.5","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.1027394"},{"key":"2024110400001175000_2024.10.30.620736v1.6","doi-asserted-by":"crossref","unstructured":"Sebastian J , Swaminath S , Nair RR et al. 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