TBAJ-876 displays bedaquiline-like mycobactericidal potency without retaining the parental drug's uncoupler activity

Jickky Palmae Sarathy; Priya Ragunathan; Christopher B. Cooper; Anna M. Upton; Gerhard Gruber; Thomas Dick

doi:10.1128/AAC.01540-19

TBAJ-876 displays bedaquiline-like mycobactericidal potency without retaining the parental drug's uncoupler activity

Jickky Palmae Sarathy, Priya Ragunathan, Christopher B. Cooper, Anna M. Upton, Gerhard Gruber^*, Thomas Dick

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

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.

Original language	English
Article number	e01540
Journal	Antimicrobial Agents and Chemotherapy
Volume	64
Issue number	2
DOIs	https://doi.org/10.1128/AAC.01540-19
Publication status	Published - Jan 27 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 American Society for Microbiology. All rights reserved.

ASJC Scopus Subject Areas

Pharmacology
Pharmacology (medical)
Infectious Diseases

Keywords

Bedaquiline
Protonophore
TBAJ-876
Tuberculosis
Uncoupler

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1128/AAC.01540-19

Cite this

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title = "TBAJ-876 displays bedaquiline-like mycobactericidal potency without retaining the parental drug's uncoupler activity",

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.",

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T1 - TBAJ-876 displays bedaquiline-like mycobactericidal potency without retaining the parental drug's uncoupler activity

AU - Sarathy, Jickky Palmae

AU - Ragunathan, Priya

AU - Cooper, Christopher B.

AU - Upton, Anna M.

AU - Gruber, Gerhard

AU - Dick, Thomas

PY - 2020/1/27

Y1 - 2020/1/27

N2 - 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.

AB - 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.

KW - Bedaquiline

KW - Protonophore

KW - TBAJ-876

KW - Tuberculosis

KW - Uncoupler

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TBAJ-876 displays bedaquiline-like mycobactericidal potency without retaining the parental drug's uncoupler activity

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

UN SDGs

Access to Document

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