{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:50:07Z","timestamp":1791237007141,"version":"4.1.0"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Previous studies indicated that inhibition of efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of antituberculosis (anti-TB) drugs against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n            in\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            combination studies. When used alone, timcodar weakly inhibited\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            growth in broth culture (MIC, 19 \u03bcg\/ml); however, it demonstrated synergism in drug combination studies with rifampin, bedaquiline, and clofazimine but not with other anti-TB agents. When\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            was cultured in host macrophage cells, timcodar had about a 10-fold increase (50% inhibitory concentration, 1.9 \u03bcg\/ml) in the growth inhibition of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            and demonstrated synergy with rifampin, moxifloxacin, and bedaquiline. In a mouse model of tuberculosis lung infection, timcodar potentiated the efficacies of rifampin and isoniazid, conferring 1.0 and 0.4 log\n            <jats:sub>10<\/jats:sub>\n            reductions in bacterial burden in lung, respectively, compared to the efficacy of each drug alone. Furthermore, timcodar reduced the likelihood of a relapse infection when evaluated in a mouse model of long-term, chronic infection with treatment with a combination of rifampin, isoniazid, and timcodar. Although timcodar had no effect on the pharmacokinetics of rifampin in plasma and lung, it did increase the plasma exposure of bedaquiline. These data suggest that the antimycobacterial drug-potentiating activity of timcodar is complex and drug dependent and involves both bacterial and host-targeted mechanisms. Further study of the improvement of the potency of antimycobacterial drugs and drug candidates when used in combination with timcodar is warranted.\n          <\/jats:p>","DOI":"10.1128\/aac.04271-14","type":"journal-article","created":{"date-parts":[[2014,12,23]],"date-time":"2014-12-23T03:11:33Z","timestamp":1419304293000},"page":"1534-1541","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":39,"title":["The Efflux Pump Inhibitor Timcodar Improves the Potency of Antimycobacterial Agents"],"prefix":"10.1128","volume":"59","author":[{"given":"Trudy H.","family":"Grossman","sequence":"first","affiliation":[{"name":"Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Shoen","sequence":"additional","affiliation":[{"name":"Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Jones","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Jones","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Cynamon","sequence":"additional","affiliation":[{"name":"Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Locher","sequence":"additional","affiliation":[{"name":"Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Global tuberculosis report 2013","author":"WHO","year":"2013","unstructured":"WHO. 2013. 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