Bactericidal mode of action of bedaquiline

  • Hards K
  • Robson J
  • Berney M
 et al. 
  • 94

    Readers

    Mendeley users who have this article in their library.
  • 42

    Citations

    Citations of this article.

Abstract

Objectives: It is not fully understood whyinhibiting ATP synthesis in Mycobacterium species leads to death in non- replicating cells.We investigated the bactericidal mode of action of the anti-tubercular F1Fo-ATP synthase inhibi- tor bedaquiline (SirturoTM) in order to further understand the lethality of ATP synthase inhibition. Methods: Mycobacterium smegmatis strains were used for all the experiments. Growth and survival during a bedaquiline challengewere performed in multiple media types. A time-course microarraywas performed during initial bedaquiline challenge in minimal medium. Oxygen consumption and proton-motive force measurements were performed on whole cells and inverted membrane vesicles, respectively. Results: A killing of 3 log10 cfu/mL was achieved 4-fold more quickly in minimal medium (a glycerol carbon source) versus rich medium (LB with Tween 80) during bedaquiline challenge. Assessing the accelerated killing condition, we identified a transcriptional remodelling of metabolism that was consistent with respiratory dys- function but inconsistent with ATP depletion. In glycerol-energized cell suspensions, bedaquiline caused an immediate 2.3-fold increase in oxygen consumption. Bedaquiline collapsed the transmembrane pH gradient, but not the membrane potential, in a dose-dependent manner. Both these effects were dependent on binding to the F1Fo-ATP synthase. Conclusions: Challenge with bedaquiline results in an electroneutral uncoupling of respiration-driven ATP synthe- sis. This may be a determinant of the bactericidal effects of bedaquiline, while ATP depletion may be a determin- ant of its delayed onset of killing.We propose that bedaquiline binds to and perturbs the a-c subunit interface of the Fo, leading to futile proton cycling, which is known to be lethal to mycobacteria.

Author-supplied keywords

  • Antimycobacterial agents
  • F1Fo-ATP synthase
  • Mycobacteria
  • R207910
  • TMC207

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free