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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4092087?pdf=render |
| _version_ | 1828335051750768640 |
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| author | Koen Andries Cristina Villellas Nele Coeck Kim Thys Tom Gevers Luc Vranckx Nacer Lounis Bouke C de Jong Anil Koul |
| author_facet | Koen Andries Cristina Villellas Nele Coeck Kim Thys Tom Gevers Luc Vranckx Nacer Lounis Bouke C de Jong Anil Koul |
| author_sort | Koen Andries |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T21:40:35Z |
| format | Article |
| id | doaj.art-4e20d166193842fdbc285fe8879fc250 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T21:40:35Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-4e20d166193842fdbc285fe8879fc2502022-12-22T02:28:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10213510.1371/journal.pone.0102135Acquired resistance of Mycobacterium tuberculosis to bedaquiline.Koen AndriesCristina VillellasNele CoeckKim ThysTom GeversLuc VranckxNacer LounisBouke C de JongAnil KoulBedaquiline (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.http://europepmc.org/articles/PMC4092087?pdf=render |
| spellingShingle | Koen Andries Cristina Villellas Nele Coeck Kim Thys Tom Gevers Luc Vranckx Nacer Lounis Bouke C de Jong Anil Koul Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC4092087?pdf=render |
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