Requirements for nitric oxide generation from isoniazid activation in vitro and inhibition of mycobacterial respiration in vivo.
Isoniazid (INH), a front-line antituberculosis agent, is activated by mycobacterial catalase-peroxidase KatG, converting INH into bactericidal reactive species. Here we investigated the requirements and the pathway of nitric oxide (NO*) generation during oxidative activation of INH by Mycobacterium tuberculosis KatG in vitro. We also provide in vivo evidence that INH-derived NO* can inhibit key mycobacterial respiratory enzymes, which may contribute to the overall antimycobacterial action of INH.
College of Pharmacy, Toxicology Program, University of New Mexico Health Sciences Center, Albuquerque, 87131, USA.
Graham S
GS
Timmins
Sharon
S
Master
Frank
F
Rusnak
Vojo
V
Deretic
D000154:Aconitate Hydratase / Q000378:metabolism; D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins; D002374:Catalase; D024881:Drug Resistance, Bacterial; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007538:Isoniazid / Q000378:metabolism* / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D019097:Spin Trapping; D013481:Superoxides / Q000378:metabolism
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D007521:Isocitrate Dehydrogenase; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; D003576:Electron Transport Complex IV; D000154:Aconitate Hydratase; D007538:Isoniazid