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Acquired resistance of Mycobacterium tuberculosis to bedaquiline.
- Source :
-
PloS one [PLoS One] 2014 Jul 10; Vol. 9 (7), pp. e102135. Date of Electronic Publication: 2014 Jul 10 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
Antitubercular Agents pharmacology
Antitubercular Agents therapeutic use
Bacterial Proteins metabolism
Base Sequence
Clofazimine pharmacology
Diarylquinolines therapeutic use
Genes, Bacterial
Genetic Fitness
Humans
Mice
Microbial Sensitivity Tests
Models, Biological
Molecular Sequence Data
Mutation genetics
Mycobacterium tuberculosis genetics
Mycobacterium tuberculosis isolation & purification
Reserpine pharmacology
Tuberculosis drug therapy
Tuberculosis microbiology
Up-Regulation drug effects
Verapamil pharmacology
Diarylquinolines pharmacology
Drug Resistance, Bacterial drug effects
Mycobacterium tuberculosis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25010492
- Full Text :
- https://doi.org/10.1371/journal.pone.0102135