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The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize <jats:italic>M. tuberculosis<\/jats:italic> to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR\/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain <jats:italic>M. tuberculosis<\/jats:italic> H37Rv, lead spectinamide 1599 and a broad panel of 27 antibiotics. <jats:italic>In vitro<\/jats:italic>, 1599 synergized with 11 drugs from 6 antibiotic classes. The observed synergy was tested against clinical isolates confirming synergy with Clarithromycin, Doxycycline and Clindamycin, combinations of which were taken forward for <jats:italic>in vivo<\/jats:italic> efficacy determination. Co-administration of 1599 and clarithromycin provided additional bacterial killing in a mouse model of acute tuberculosis infection, but not in a chronic infection model. Further studies indicated that mismatched drug exposure profiles likely permitted induction of phenotypic clarithromycin resistance and subsequent loss of synergism. These studies highlight the importance of validating <jats:italic>in vitro<\/jats:italic> synergism and the challenge of matching drug exposures to obtain a synergistic outcome <jats:italic>in vivo<\/jats:italic>. Results from this study indicate that a 1599 clarithromycin combination is potentially viable, providing the drug exposures can be carefully monitored.<\/jats:p>","DOI":"10.1038\/srep13985","type":"journal-article","created":{"date-parts":[[2015,9,14]],"date-time":"2015-09-14T09:49:22Z","timestamp":1442224162000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics"],"prefix":"10.1038","volume":"5","author":[{"given":"David F.","family":"Bruhn","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S.","family":"Scherman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiuyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitri","family":"Scherbakov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernd","family":"Meibohm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik C.","family":"B\u00f6ttger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne J.","family":"Lenaerts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard E.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,9,14]]},"reference":[{"key":"BFsrep13985_CR1","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1056\/NEJMra1200894","volume":"368","author":"A Zumla","year":"2013","unstructured":"Zumla, A., Raviglione, M., Hafner, R. & von Reyn, C. 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