This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Timmins, G. S. Articles by Deretic, V. Search for Related Content PubMed PubMed Citation Articles by Timmins, G. S. Articles by Deretic, V.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 2004, p. 3006-3009, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.3006-3009.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Nitric Oxide Generated from Isoniazid Activation by KatG: Source of Nitric Oxide and Activity against Mycobacterium tuberculosis

Graham S. Timmins,^1* Sharon Master,² Frank Rusnak,^3, and Vojo Deretic²

College of Pharmacy, Toxicology Program,¹ Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131,² Department of Biochemistry and Molecular Biology and Section of Hematology Research, Mayo Clinic and Foundation, Rochester, Minnesota 55905³

Received 7 January 2004/ Returned for modification 8 March 2004/ Accepted 2 April 2004

Isonicotinic acid hydrazide (INH) is a frontline antituberculosis agent. Once taken up by Mycobacterium tuberculosis, INH requires activation by the catalase-peroxidase KatG, converting INH from its prodrug form into a range of bactericidal reactive species. Here we used ¹⁵N-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 M. tuberculosis 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^·, is involved in antimycobacterial action. In conclusion, INH-derived NO^· has biological activity, which directly contributes to the antimycobacterial action of INH.

Deceased.

This article has been cited by other articles:

• Pagan-Ramos, E., Master, S. S., Pritchett, C. L., Reimschuessel, R., Trucksis, M., Timmins, G. S., Deretic, V. (2006). Molecular and Physiological Effects of Mycobacterial oxyR Inactivation.. J. Bacteriol. 188: 2674-2680 [Abstract] [Full Text]