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Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline

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-resista...

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Autores principales: Andries, Koen, Villellas, Cristina, Coeck, Nele, Thys, Kim, Gevers, Tom, Vranckx, Luc, Lounis, Nacer, de Jong, Bouke C., Koul, Anil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092087/
https://www.ncbi.nlm.nih.gov/pubmed/25010492
http://dx.doi.org/10.1371/journal.pone.0102135
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author Andries, Koen
Villellas, Cristina
Coeck, Nele
Thys, Kim
Gevers, Tom
Vranckx, Luc
Lounis, Nacer
de Jong, Bouke C.
Koul, Anil
author_facet Andries, Koen
Villellas, Cristina
Coeck, Nele
Thys, Kim
Gevers, Tom
Vranckx, Luc
Lounis, Nacer
de Jong, Bouke C.
Koul, Anil
author_sort Andries, Koen
collection PubMed
description 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.
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spelling pubmed-40920872014-07-18 Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline Andries, Koen Villellas, Cristina Coeck, Nele Thys, Kim Gevers, Tom Vranckx, Luc Lounis, Nacer de Jong, Bouke C. Koul, Anil PLoS One Research Article 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. Public Library of Science 2014-07-10 /pmc/articles/PMC4092087/ /pubmed/25010492 http://dx.doi.org/10.1371/journal.pone.0102135 Text en © 2014 Andries et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Andries, Koen
Villellas, Cristina
Coeck, Nele
Thys, Kim
Gevers, Tom
Vranckx, Luc
Lounis, Nacer
de Jong, Bouke C.
Koul, Anil
Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline
title Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline
title_full Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline
title_fullStr Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline
title_full_unstemmed Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline
title_short Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline
title_sort acquired resistance of mycobacterium tuberculosis to bedaquiline
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092087/
https://www.ncbi.nlm.nih.gov/pubmed/25010492
http://dx.doi.org/10.1371/journal.pone.0102135
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