title: Acquired resistance of Mycobacterium tuberculosis to bedaquiline.
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.
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Cristina
authors.initials: C
authors.lastname: Villellas
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Coeck
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Thys
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Gevers
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Vranckx
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Nacer
authors.initials: N
authors.lastname: Lounis
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Bouke C
authors.initials: BC
authors.lastname: de Jong
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000378:metabolism; D001483:Base Sequence; D002991:Clofazimine / Q000494:pharmacology; D064687:Diarylquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005798:Genes, Bacterial; D056084:Genetic Fitness; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D012110:Reserpine / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D015854:Up-Regulation / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D064687:Diarylquinolines; C493870:bedaquiline; D012110:Reserpine; D014700:Verapamil; D002991:Clofazimine