TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug's Uncoupler Activity

Antimicrob Agents Chemother. 2020 Jan 27;64(2):e01540-19. doi: 10.1128/AAC.01540-19. Print 2020 Jan 27.

Abstract

The diarylquinoline F1FO-ATP synthase inhibitor bedaquiline (BDQ) displays protonophore activity. Thus, uncoupling electron transport from ATP synthesis appears to be a second mechanism of action of this antimycobacterial drug. Here, we show that the new BDQ analogue TBAJ-876 did not retain the parental drug's protonophore activity. Comparative time-kill analyses revealed that both compounds exert the same bactericidal activity. These results suggest that the uncoupler activity is not required for the bactericidal activity of diarylquinolines.

Keywords: TBAJ-876; bedaquiline; protonophore; tuberculosis; uncoupler.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Antitubercular Agents / pharmacology*
  • Diarylquinolines / pharmacology*
  • Electron Transport / drug effects
  • Lipid Bilayers
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Protons
  • Uncoupling Agents / pharmacology*

Substances

  • Antitubercular Agents
  • Diarylquinolines
  • Lipid Bilayers
  • Protons
  • TBAJ-876
  • Uncoupling Agents
  • bedaquiline
  • Adenosine Triphosphate