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

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

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

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

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: J Biol Chem, 2024, 300, (2), pp. 105618
Issue Date:: 2024-02

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Field	Value	Language
dc.contributor.author	Ragunathan, P
dc.contributor.author	Sae-Lao, P
dc.contributor.author	Hamela, C
dc.contributor.author	Alcaraz, M
dc.contributor.author	Krah, A
dc.contributor.author	Poh, WH
dc.contributor.author	Ern Pee, CJ
dc.contributor.author	Hou Lim, AY
dc.contributor.author	Rice, SA
dc.contributor.author	Pethe, K
dc.contributor.author	Bond, PJ
dc.contributor.author	Dick, T
dc.contributor.author	Kremer, L
dc.contributor.author	Bates, RW
dc.contributor.author	Grüber, G
dc.date.accessioned	2024-12-17T06:20:27Z
dc.date.available	2023-12-22
dc.date.available	2024-12-17T06:20:27Z
dc.date.issued	2024-02
dc.identifier.citation	J Biol Chem, 2024, 300, (2), pp. 105618
dc.identifier.issn	0021-9258
dc.identifier.issn	1083-351X
dc.identifier.uri	http://hdl.handle.net/10453/182666
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	J Biol Chem
dc.relation.isbasedon	10.1016/j.jbc.2023.105618
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.classification	31 Biological sciences
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.classification	34 Chemical sciences
dc.subject.mesh	Humans
dc.subject.mesh	Adenosine Triphosphate
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Azabicyclo Compounds
dc.subject.mesh	Carbapenems
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Mycobacterium Infections, Nontuberculous
dc.subject.mesh	Nontuberculous Mycobacteria
dc.subject.mesh	Diarylquinolines
dc.subject.mesh	Humans
dc.subject.mesh	Carbapenems
dc.subject.mesh	Adenosine Triphosphate
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Azabicyclo Compounds
dc.subject.mesh	Mycobacterium Infections, Nontuberculous
dc.subject.mesh	Nontuberculous Mycobacteria
dc.subject.mesh	Diarylquinolines
dc.subject.mesh	Humans
dc.subject.mesh	Adenosine Triphosphate
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Azabicyclo Compounds
dc.subject.mesh	Carbapenems
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Mycobacterium Infections, Nontuberculous
dc.subject.mesh	Nontuberculous Mycobacteria
dc.subject.mesh	Diarylquinolines
dc.title	High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo.
dc.type	Journal Article
utslib.citation.volume	300
utslib.location.activity	United States
utslib.for	03 Chemical Sciences
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Institute for Microbiology & Infection (AIMI)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Institute for Microbiology & Infection (AIMI)/Australian Institute for Microbiology & Infection (AIMI) Associate Members
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-12-17T06:20:24Z
pubs.issue	2
pubs.publication-status	Published
pubs.volume	300
utslib.citation.issue	2

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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http://hdl.handle.net/10453/182666