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Acquired resistance of Mycobacterium tuberculosis to bedaquiline

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dc.contributor.author Andries, K. en_US
dc.contributor.author Villellas, C. en_US
dc.contributor.author Coeck, N. en_US
dc.contributor.author Thys, K. en_US
dc.contributor.author Gevers, T. en_US
dc.contributor.author Vranckx, L. en_US
dc.contributor.author Lounis, N. en_US
dc.contributor.author de Jong, B. C. en_US
dc.contributor.author Koul, A. en_US
dc.date.accessioned 2014-09-25T13:39:41Z
dc.date.available 2014-09-25T13:39:41Z
dc.date.issued 2014 en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0102135 en_US
dc.identifier.other ITG-B3B; ITG-B8A; DBM; U-MYCOB; JIF; DOI; FTA; E-only; Abstract; UPD56 en_US
dc.identifier.uri http://hdl.handle.net/10390/7804
dc.description.abstract Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications. en_US
dc.language English en_US
dc.subject Bacterial diseases en_US
dc.subject Tuberculosis en_US
dc.subject Mycobacterium tuberculosis en_US
dc.subject Vaccine development en_US
dc.subject Drug resistance en_US
dc.subject Acquired immunity en_US
dc.subject Bedaquiline en_US
dc.subject Cross-resistance en_US
dc.subject Clofazimine en_US
dc.subject Mutations en_US
dc.subject Inhibitory activity en_US
dc.title Acquired resistance of Mycobacterium tuberculosis to bedaquiline en_US
dc.type Article-E en_US
dc.citation.issue 7 en_US
dc.citation.jtitle PLoS ONE en_US
dc.citation.volume 9 en_US
dc.citation.pages e102135 en_US
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/25010492 en_US
dc.citation.jabbreviation PLoS ONE en_US


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