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

Nabila Ismail, Nazir A. Ismail, Shaheed Omar, Remco P. H. Peters*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)

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 mu g/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 otpE mutations.

Original languageEnglish
Article numberARTN e00292-19
Pages (from-to)1-6
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number8
DOIs
Publication statusPublished - Aug 2019

Keywords

  • Mycobacterium tuberculosis
  • atpE
  • bedaquiline
  • in vitro model
  • rv0678
  • stepwise acquisition
  • MYCOBACTERIUM-TUBERCULOSIS
  • CLOFAZIMINE
  • VARIANTS
  • SYNTHASE

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