Acquired resistance of Mycobacterium tuberculosis to bedaquiline

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

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

Grant support

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.