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

Center for Discovery and Innovation

National University of Singapore
Nanyang Technological University
Global Alliance for TB Drug Development (TB Alliance)

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

31 Scopus citations

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
State	Published - 27 Jan 2020

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Bedaquiline
Protonophore
TBAJ-876
Tuberculosis
Uncoupler

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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.",

keywords = "Bedaquiline, Protonophore, TBAJ-876, Tuberculosis, Uncoupler",

author = "Sarathy, \{Jickky Palmae\} and Priya Ragunathan and Cooper, \{Christopher B.\} and Upton, \{Anna M.\} and Gerhard Gruber and Thomas Dick",

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doi = "10.1128/AAC.01540-19",

language = "English",

volume = "64",

journal = "Antimicrobial Agents and Chemotherapy",

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publisher = "American Society for Microbiology",

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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

UR - https://www.scopus.com/pages/publications/85078571665

U2 - 10.1128/AAC.01540-19

DO - 10.1128/AAC.01540-19

M3 - Article

C2 - 31712198

AN - SCOPUS:85078571665

SN - 0066-4804

VL - 64

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 2

M1 - e01540

ER -

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

Abstract

UN SDGs

Keywords

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