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Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several antituberculosis (anti-TB) drugs\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            . This potentiation is widely attributed to inhibition of the efflux pumps of\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            , resulting in intrabacterial drug accumulation. Here, we confirmed and quantified verapamil's synergy with several anti-TB drugs, including bedaquiline (BDQ) and clofazimine (CFZ), but found that the effect is not due to increased intrabacterial drug accumulation. We show that, consistent with its\n            <jats:italic>in vitro<\/jats:italic>\n            potentiating effects on anti-TB drugs that target or require oxidative phosphorylation, the cationic amphiphile verapamil disrupts membrane function and induces a membrane stress response similar to those seen with other membrane-active agents. We recapitulated these activities\n            <jats:italic>in vitro<\/jats:italic>\n            using inverted mycobacterial membrane vesicles, indicating a direct effect of verapamil on membrane energetics. We observed bactericidal activity against nonreplicating \u201cpersister\u201d\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            that was consistent with such a mechanism of action. In addition, we demonstrated a pharmacokinetic interaction whereby human-equivalent doses of verapamil caused a boost of rifampin exposure in mice, providing a potential explanation for the observed treatment-shortening effect of verapamil in mice receiving first-line drugs. Our findings thus elucidate the mechanistic basis for verapamil's potentiation of anti-TB drugs\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            and highlight a previously unrecognized role for the membrane of\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            as a pharmacologic target.\n          <\/jats:p>","DOI":"10.1128\/aac.02107-17","type":"journal-article","created":{"date-parts":[[2018,2,19]],"date-time":"2018-02-19T14:29:47Z","timestamp":1519050587000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":109,"title":["Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis"],"prefix":"10.1128","volume":"62","author":[{"given":"Chao","family":"Chen","sequence":"first","affiliation":[{"name":"Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Gardete","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College, Weill Department of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Sander","family":"Jansen","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College, Weill Department of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annanya","family":"Shetty","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9604-9452","authenticated-orcid":false,"given":"Thomas","family":"Dick","sequence":"additional","affiliation":[{"name":"Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA"},{"name":"Department of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu Y.","family":"Rhee","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College, Weill Department of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Dartois","sequence":"additional","affiliation":[{"name":"Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA"},{"name":"Department of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Global tuberculosis report","author":"WHO","year":"2016","unstructured":"WHO. 2016. 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Targeting phenotypically tolerant Mycobacterium tuberculosis p 317\u2013360. In Jacobs W Jr McShane H Mizrahi V Orme I (ed) Tuberculosis and the tubercle bacillus 2nd ed. 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