Mechanisms of action of isoniazid.
For decades after its introduction, the mechanisms of action of the front-line antituberculosis therapeutic agent isoniazid (INH) remained unclear. Recent developments have shown that peroxidative activation of isoniazid by the mycobacterial enzyme KatG generates reactive species that form adducts with NAD(+) and NADP(+) that are potent inhibitors of lipid and nucleic acid biosynthetic enzymes. A direct role for some isoniazid-derived reactive species, such as nitric oxide, in inhibiting mycobacterial metabolic enzymes has also been shown. The concerted effects of these activities - inhibition of cell wall lipid synthesis, depletion of nucleic acid pools and metabolic depression - drive the exquisite potency and selectivity of this agent. To understand INH action and resistance fully, a synthesis of knowledge is required from multiple separate lines of research - including molecular genetic approaches, in vitro biochemical studies and free radical chemistry - which is the intent of this review.
Timmins
Graham S
GS
College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. gtimmins@salud.umn.edu
Deretic
Vojo
V
D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000378:metabolism
D000995:Antitubercular Agents; D009243:NAD; D007538:Isoniazid