2. Academic Validation
  3. TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug's Uncoupler Activity

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.
Jickky Palmae Sarathy 1,  Priya Ragunathan 2,  Christopher B Cooper 3,  Anna M Upton 3,  Gerhard Grüber 4,  Thomas Dick 5 6
Affiliations

Affiliations

  • 1 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 2 School of Biological Sciences, Nanyang Technological University, Singapore.
  • 3 Global Alliance for TB Drug Development (TB Alliance), New York, New York, USA.
  • 4 School of Biological Sciences, Nanyang Technological University, Singapore GGrueber@ntu.edu.sg thomas.dick@hmh-cdi.org.
  • 5 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore GGrueber@ntu.edu.sg thomas.dick@hmh-cdi.org.
  • 6 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
PMID: 31712198 DOI: 10.1128/AAC.01540-19
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.

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