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.
Highlights
The diarylquinoline F1FO-ATP synthase inhibitor bedaquiline (BDQ) displays protonophore activity
To determine whether TBAJ-876 displays protonophore activity, we measured the effect of the compound on the transmembrane pH gradient of mycobacterial inverted vesicles using the pH-responsive fluorophore 9-amino-6-chloro-2-methoxyacridine (ACMA) (Sigma-Aldrich, USA) as described previously [9]
The weaker protonophore activity of TBAJ-876 may be a result of its less lipophilic character, limiting its ability to diffuse through lipid-rich membranes and preventing it from acting as an efficient proton translocator
Summary
The diarylquinoline F1FO-ATP synthase inhibitor bedaquiline (BDQ) displays protonophore activity. To determine whether TBAJ-876 displays protonophore activity, we measured the effect of the compound on the transmembrane pH gradient of mycobacterial inverted vesicles using the pH-responsive fluorophore 9-amino-6-chloro-2-methoxyacridine (ACMA) (Sigma-Aldrich, USA) as described previously [9]. These results confirm that BDQ displays protonophore activity and uncouples electron transport from ATP synthesis.
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