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Bedaquiline resistance typically arises through mutations in\n                  <jats:italic>Rv0678<\/jats:italic>\n                  that upregulate drug efflux and confer cross-resistance to multiple drug classes. Here, we identify and optimise a chemical series targeting MenG, a central enzyme in the menaquinone biosynthesis pathway, yielding potent bactericidal inhibitors with\n                  <jats:italic>in vivo<\/jats:italic>\n                  efficacy. Strikingly, MenG inhibition restored bedaquiline susceptibility in efflux-mediated resistant strains, an effect confirmed\n                  <jats:italic>in vivo<\/jats:italic>\n                  where combination therapy achieved a 99.8% reduction in bacterial burden compared with bedaquiline alone. Potentiation also extended to pretomanid and other key agents. Disruption of upstream menaquinone and shikimate pathway enzymes produced similar resensitisation, establishing these pathways as tractable targets for restoring drug susceptibility in\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  . These findings provide a novel strategy to overcome bedaquiline resistance and strengthen future regimens for efflux-mediated drug-resistant tuberculosis.\n                <\/jats:p>","DOI":"10.64898\/2026.02.10.702511","type":"posted-content","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T03:21:09Z","timestamp":1770780069000},"source":"Crossref","is-referenced-by-count":0,"title":["Menaquinone depletion resensitises bedaquiline-resistant tuberculosis"],"prefix":"10.64898","author":[{"given":"Jennefer","family":"Wetzel","sequence":"first","affiliation":[{"name":"Johnson & Johnson, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Dallow","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellie","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William H.","family":"Pearson","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stijn","family":"Daems","sequence":"additional","affiliation":[{"name":"Johnson & Johnson, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Govaerts","sequence":"additional","affiliation":[{"name":"Johnson & Johnson, Beerse, Belgium"},{"name":"Charles River Laboratories, Turnhoutseweg 30, 2340, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce","family":"Hereijgers","sequence":"additional","affiliation":[{"name":"Charles River Laboratories, Turnhoutseweg 30, 2340, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joke","family":"Sprangers","sequence":"additional","affiliation":[{"name":"Charles River Laboratories, Turnhoutseweg 30, 2340, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry","family":"Truebody","sequence":"additional","affiliation":[{"name":"Africa Health Research Institute, University of KwaZulu Natal, Durban, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie","family":"Maes","sequence":"additional","affiliation":[{"name":"Johnson & Johnson, Beerse, Belgium"},{"name":"VIB-KU Leuven Center for Microbiology, 3001, Heverlee, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera","family":"van Hasselt","sequence":"additional","affiliation":[{"name":"Charles River Laboratories, Turnhoutseweg 30, 2340, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annelies","family":"Leemans","sequence":"additional","affiliation":[{"name":"Johnson & Johnson, Beerse, Belgium"},{"name":"Charles River Laboratories, Turnhoutseweg 30, 2340, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venugopal","family":"Pujari","sequence":"additional","affiliation":[{"name":"Microbiology, Immunology, and Pathology Department, Colorado State University, Fort Collins, CO, 80523, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Vos","sequence":"additional","affiliation":[{"name":"Johnson & Johnson, Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos M.","family":"Mart\u00ednez Viturro","sequence":"additional","affiliation":[{"name":"Global Discovery Chemistry, Janssen-Cilag SA, a Johnson & Johnson company, C. 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