High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo

Priya Ragunathan; Patcharaporn Sae-Lao; Claire Hamela; Matthéo Alcaraz; Alexander Krah; Wee Han Poh; Carmen Jia Ern Pee; Albert Yick Hou Lim; Scott A. Rice; Kevin Pethe; Peter J. Bond; Thomas Dick; Laurent Kremer; Roderick W. Bates; Gerhard Grüber

doi:10.1016/j.jbc.2023.105618

High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo

Priya Ragunathan, Patcharaporn Sae-Lao, Claire Hamela, Matthéo Alcaraz, Alexander Krah, Wee Han Poh, Carmen Jia Ern Pee, Albert Yick Hou Lim, Scott A. Rice, Kevin Pethe, Peter J. Bond, Thomas Dick, Laurent Kremer^*, Roderick W. Bates, Gerhard Grüber

^*Corresponding author for this work

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

4 Citations (Scopus)

Abstract

The F₁F_O-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the F_O domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem–avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307–tebipenem–avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.

Original language	English
Article number	105618
Journal	Journal of Biological Chemistry
Volume	300
Issue number	2
DOIs	https://doi.org/10.1016/j.jbc.2023.105618
Publication status	Published - Feb 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2024 The Authors

ASJC Scopus Subject Areas

Biochemistry
Molecular Biology
Cell Biology

Keywords

antibiotics
ATP synthesis
bacterial pathogenesis
membrane protein
mycobacteria
nontuberculosis mycobacterium

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10.1016/j.jbc.2023.105618

Cite this

Ragunathan, P., Sae-Lao, P., Hamela, C., Alcaraz, M., Krah, A., Poh, W. H., Ern Pee, C. J., Hou Lim, A. Y., Rice, S. A., Pethe, K., Bond, P. J., Dick, T., Kremer, L., Bates, R. W., & Grüber, G. (2024). High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo. Journal of Biological Chemistry, 300(2), Article 105618. https://doi.org/10.1016/j.jbc.2023.105618

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abstract = "The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem–avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307–tebipenem–avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.",

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author = "Priya Ragunathan and Patcharaporn Sae-Lao and Claire Hamela and Matth{\'e}o Alcaraz and Alexander Krah and Poh, {Wee Han} and {Ern Pee}, {Carmen Jia} and {Hou Lim}, {Albert Yick} and Rice, {Scott A.} and Kevin Pethe and Bond, {Peter J.} and Thomas Dick and Laurent Kremer and Bates, {Roderick W.} and Gerhard Gr{\"u}ber",

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doi = "10.1016/j.jbc.2023.105618",

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Ragunathan, P, Sae-Lao, P, Hamela, C, Alcaraz, M, Krah, A, Poh, WH, Ern Pee, CJ, Hou Lim, AY, Rice, SA, Pethe, K, Bond, PJ, Dick, T, Kremer, L, Bates, RW & Grüber, G 2024, 'High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo', Journal of Biological Chemistry, vol. 300, no. 2, 105618. https://doi.org/10.1016/j.jbc.2023.105618

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T1 - High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo

AU - Ragunathan, Priya

AU - Sae-Lao, Patcharaporn

AU - Hamela, Claire

AU - Alcaraz, Matthéo

AU - Krah, Alexander

AU - Poh, Wee Han

AU - Ern Pee, Carmen Jia

AU - Hou Lim, Albert Yick

AU - Rice, Scott A.

AU - Pethe, Kevin

AU - Bond, Peter J.

AU - Dick, Thomas

AU - Kremer, Laurent

AU - Bates, Roderick W.

AU - Grüber, Gerhard

PY - 2024/2

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N2 - The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem–avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307–tebipenem–avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.

AB - The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem–avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307–tebipenem–avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.

KW - antibiotics

KW - ATP synthesis

KW - bacterial pathogenesis

KW - membrane protein

KW - mycobacteria

KW - nontuberculosis mycobacterium

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High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

Access to Document

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Investigators at Nanyang Technological University Report Findings in Life Science (High Efficacy of the F-atp Synthase Inhibitor Tbaj-5307 Nontuberculous In Vitro And In Vivo )

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High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

Access to Document

Other files and links

Fingerprint

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Investigators at Nanyang Technological University Report Findings in Life Science (High Efficacy of the F-atp Synthase Inhibitor Tbaj-5307 Nontuberculous In Vitro And In Vivo )

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