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Media type:
E-Article
Title:
Nitric Oxide Generated from Isoniazid Activation by KatG: Source of Nitric Oxide and Activity againstMycobacterium tuberculosis
Contributor:
Timmins, Graham S.;
Master, Sharon;
Rusnak, Frank;
Deretic, Vojo
Published:
American Society for Microbiology, 2004
Published in:
Antimicrobial Agents and Chemotherapy, 48 (2004) 8, Seite 3006-3009
Language:
English
DOI:
10.1128/aac.48.8.3006-3009.2004
ISSN:
0066-4804;
1098-6596
Origination:
Footnote:
Description:
<jats:title>ABSTRACT</jats:title><jats:p>Isonicotinic acid hydrazide (INH) is a frontline antituberculosis agent. Once taken up by<jats:italic>Mycobacterium tuberculosis</jats:italic>, INH requires activation by the catalase-peroxidase KatG, converting INH from its prodrug form into a range of bactericidal reactive species. Here we used<jats:sup>15</jats:sup>N-labeled INH together with electron paramagnetic resonance spin trapping techniques to demonstrate that nitric oxide (NO˙) is generated from oxidation at the hydrazide nitrogens during the activation of INH by<jats:italic>M. tuberculosis</jats:italic>KatG. We also observed that a specific scavenger of NO˙ provided protection against the antimycobacterial activity of INH in bacterial culture. No significant increases in mycobacterial protein nitration were detected, suggesting that NO˙ and not peroxynitrite, a nitrating metabolite of NO<jats:sup>·</jats:sup>, is involved in antimycobacterial action. In conclusion, INH-derived NO<jats:sup>·</jats:sup>has biological activity, which directly contributes to the antimycobacterial action of INH.</jats:p>