The cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden in vivo through host and bacterial targets.

Black, HD; Xu, W; Hortle, E; Robertson, SI; Britton, WJ; Kaur, A; New, EJ; Witting, PK; Chami, B; Oehlers, SH

The cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden in vivo through host and bacterial targets.

Black, HD Xu, W Hortle, E

Robertson, SI Britton, WJ Kaur, A New, EJ Witting, PK Chami, B Oehlers, SH

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Free Radical Biology and Medicine, 2019, 135, pp. 157-166
Issue Date:: 2019-05-01

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Field	Value	Language
dc.contributor.author	Black, HD
dc.contributor.author	Xu, W
dc.contributor.author	Hortle, E https://orcid.org/0000-0001-9633-5638
dc.contributor.author	Robertson, SI
dc.contributor.author	Britton, WJ
dc.contributor.author	Kaur, A
dc.contributor.author	New, EJ
dc.contributor.author	Witting, PK
dc.contributor.author	Chami, B
dc.contributor.author	Oehlers, SH
dc.date.accessioned	2022-07-26T05:52:09Z
dc.date.available	2019-03-09
dc.date.available	2022-07-26T05:52:09Z
dc.date.issued	2019-05-01
dc.identifier.citation	Free Radical Biology and Medicine, 2019, 135, pp. 157-166
dc.identifier.issn	0891-5849
dc.identifier.issn	1873-4596
dc.identifier.uri	http://hdl.handle.net/10453/159164
dc.description.abstract	Tuberculosis is a chronic inflammatory disease caused by persistent infection with Mycobacterium tuberculosis. The rise of antibiotic resistant strains necessitates the design of novel treatments. Recent evidence shows that not only is M. tuberculosis highly resistant to oxidative killing, it also co-opts host oxidant production to induce phagocyte death facilitating bacterial dissemination. We have targeted this redox environment with the cyclic nitroxide derivative 4-methoxy-TEMPO (MetT) in the zebrafish-M. marinum infection model. MetT inhibited the production of mitochondrial ROS and decreased infection-induced cell death to aid containment of infection. We identify a second mechanism of action whereby stress conditions, including hypoxia, found in the infection microenvironment appear to sensitise M. marinum to killing by MetT both in vitro and in vivo. Together, our study demonstrates MetT inhibited the growth and dissemination of M. marinum through host and bacterial targets.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Free Radical Biology and Medicine
dc.relation.isbasedon	10.1016/j.freeradbiomed.2019.03.010
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.mesh	Animals
dc.subject.mesh	Antioxidants
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Cyclic N-Oxides
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Humans
dc.subject.mesh	Macrophages
dc.subject.mesh	Mycobacterium marinum
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Tuberculosis
dc.subject.mesh	Zebrafish
dc.subject.mesh	Animals
dc.subject.mesh	Antioxidants
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Cyclic N-Oxides
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Humans
dc.subject.mesh	Macrophages
dc.subject.mesh	Mycobacterium marinum
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Tuberculosis
dc.subject.mesh	Zebrafish
dc.subject.mesh	Macrophages
dc.subject.mesh	Animals
dc.subject.mesh	Zebrafish
dc.subject.mesh	Humans
dc.subject.mesh	Mycobacterium marinum
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Tuberculosis
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Cyclic N-Oxides
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Antioxidants
dc.title	The cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden in vivo through host and bacterial targets.
dc.type	Journal Article
utslib.citation.volume	135
utslib.location.activity	United States
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1101 Medical Biochemistry and Metabolomics
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-07-26T05:52:05Z
pubs.publication-status	Published
pubs.volume	135

Abstract:

Tuberculosis is a chronic inflammatory disease caused by persistent infection with Mycobacterium tuberculosis. The rise of antibiotic resistant strains necessitates the design of novel treatments. Recent evidence shows that not only is M. tuberculosis highly resistant to oxidative killing, it also co-opts host oxidant production to induce phagocyte death facilitating bacterial dissemination. We have targeted this redox environment with the cyclic nitroxide derivative 4-methoxy-TEMPO (MetT) in the zebrafish-M. marinum infection model. MetT inhibited the production of mitochondrial ROS and decreased infection-induced cell death to aid containment of infection. We identify a second mechanism of action whereby stress conditions, including hypoxia, found in the infection microenvironment appear to sensitise M. marinum to killing by MetT both in vitro and in vivo. Together, our study demonstrates MetT inhibited the growth and dissemination of M. marinum through host and bacterial targets.

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http://hdl.handle.net/10453/159164