Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism

Nat Commun. 2014 Feb 26;5:3369. doi: 10.1038/ncomms4369.


Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. Though BDQ has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week of chemotherapy is minimal. Here, using microfluidic devices and time-lapse microscopy of Mycobacterium tuberculosis, we confirm the absence of significant bacteriolytic activity during the first 3-4 days of exposure to BDQ. BDQ-induced inhibition of ATP synthesis leads to bacteriostasis within hours after drug addition. Transcriptional and proteomic analyses reveal that M. tuberculosis responds to BDQ by induction of the dormancy regulon and activation of ATP-generating pathways, thereby maintaining bacterial viability during initial drug exposure. BDQ-induced bacterial killing is significantly enhanced when the mycobacteria are grown on non-fermentable energy sources such as lipids (impeding ATP synthesis via glycolysis). Our results show that BDQ exposure triggers a metabolic remodelling in mycobacteria, thereby enabling transient bacterial survival.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Diarylquinolines / pharmacology*
  • Dose-Response Relationship, Drug
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Bacterial / drug effects*
  • Glycolysis / drug effects*
  • Microbial Viability / drug effects
  • Microbial Viability / genetics
  • Microfluidic Analytical Techniques
  • Microscopy, Fluorescence
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Proteome / genetics
  • Proteome / metabolism
  • Proteomics / methods
  • Reverse Transcriptase Polymerase Chain Reaction
  • Single-Cell Analysis / methods
  • Time Factors
  • Time-Lapse Imaging


  • Antitubercular Agents
  • Bacterial Proteins
  • Diarylquinolines
  • Proteome
  • bedaquiline
  • Adenosine Triphosphate

Associated data

  • GEO/GSE43749