Acquired resistance of Mycobacterium tuberculosis to bedaquiline
Koen Andries, Cristina Villellas, Nele Coeck, Kim Thys, Tom Gevers, Luc Vranckx, Nacer Lounis, Bouke C de Jong, Anil Koul, Koen Andries, Cristina Villellas, Nele Coeck, Kim Thys, Tom Gevers, Luc Vranckx, Nacer Lounis, Bouke C de Jong, Anil Koul
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.
Conflict of interest statement
Competing Interests: KA, CV, KT, TG, LV, NL and AK are currently under the employment of Janssen Pharmaceutica, which provided funds and equipment to conduct the studies and where they receive salary, benefits and stock (KA and AK). This does not alter the authors′ adherence to all PLOS ONE policies on sharing data and materials; for the avoidance of doubt this does not include bedaquiline samples or patient isolates.
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Source: PubMed