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.
Timmins
Graham S
GS
College of Pharmacy, Toxicology Program, University of New Mexico Health Sciences Center, Albuquerque, 87131, USA.
Master
Sharon
S
Rusnak
Frank
F
Deretic
Vojo
V
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