1. Academic Validation
  2. Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis

Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis

  • Antimicrob Agents Chemother. 2004 Aug;48(8):3006-9. doi: 10.1128/AAC.48.8.3006-3009.2004.
Graham S Timmins 1 Sharon Master Frank Rusnak Vojo Deretic
Affiliations

Affiliation

  • 1 College of Pharmacy, Toxicology Program, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA. gtimmins@salud.unm.edu
Abstract

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 NOdot; 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.

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