In Vitro Study of Stepwise Acquisition of rv0678 and atpE Mutations Conferring Bedaquiline Resistance

Antimicrob Agents Chemother. 2019 Jul 25;63(8):e00292-19. doi: 10.1128/AAC.00292-19. Print 2019 Aug.

Abstract

Bedaquiline resistance within Mycobacterium tuberculosis may arise through efflux-based (rv0678) or target-based (atpE) pathway mutations. M. tuberculosis mutant populations from each of five sequential steps in a passaging approach, using a pyrazinamide-resistant ATCC strain, were subjected to MIC determinations and whole-genome sequencing. Exposure to increasing bedaquiline concentrations resulted in increasing phenotypic resistance (up to >2 μg/ml) through MIC determination on solid medium (Middlebrook 7H10). rv0678 mutations were dynamic, while atpE mutations were fixed, once occurring. We present the following hypothesis for in vitro emergence of bedaquiline resistance: rv0678 mutations may be the first transient step in low-level resistance acquisition, followed by high-level resistance due to fixed atpE mutations.

Keywords: Mycobacterium tuberculosis; atpE; bedaquiline; in vitro model; rv0678; stepwise acquisition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / genetics*
  • Bacterial Proton-Translocating ATPases / genetics
  • Diarylquinolines / pharmacology*
  • Drug Resistance, Bacterial / drug effects*
  • Drug Resistance, Bacterial / genetics
  • Microbial Sensitivity Tests
  • Mutation*
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Diarylquinolines
  • bedaquiline
  • Bacterial Proton-Translocating ATPases