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
  • 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 [email protected] [email protected].
  • 5. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [email protected] [email protected].
  • 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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