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

doi:10.1371/journal.pone.0102135

Acquired resistance of Mycobacterium tuberculosis to bedaquiline

PLoS One. 2014 Jul 10;9(7):e102135. doi: 10.1371/journal.pone.0102135. eCollection 2014.

Authors

Koen Andries¹, Cristina Villellas¹, Nele Coeck², Kim Thys¹, Tom Gevers¹, Luc Vranckx¹, Nacer Lounis¹, Bouke C de Jong², Anil Koul¹

Affiliations

¹ Department of Infectious Diseases, Janssen Pharmaceutica, Beerse, Belgium.
² Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / pharmacology
Antitubercular Agents / therapeutic use
Bacterial Proteins / metabolism
Base Sequence
Clofazimine / pharmacology
Diarylquinolines / pharmacology*
Diarylquinolines / therapeutic use
Drug Resistance, Bacterial / drug effects*
Genes, Bacterial
Genetic Fitness
Humans
Mice
Microbial Sensitivity Tests
Models, Biological
Molecular Sequence Data
Mutation / genetics
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / genetics
Mycobacterium tuberculosis / isolation & purification
Reserpine / pharmacology
Tuberculosis / drug therapy
Tuberculosis / microbiology
Up-Regulation / drug effects
Verapamil / pharmacology

Substances

Antitubercular Agents
Bacterial Proteins
Diarylquinolines
bedaquiline
Reserpine
Verapamil
Clofazimine

Associated data

SRA/SRP042318
SRA/SRP042320
SRA/SRP042321

Grants and funding

BdJ received funds from Janssen for drug susceptibility testing on isolates from clinical studies on bedaquiline. NC is funded by a Baekeland PhD scholarship from the Flemish Institute for Scientific Technology (IWT 130308). The funder provided support in the form of salaries for NC, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors are articulated in the ‘author contributions’ section.