Mechanisms of action of isoniazid
Article first published online: 11 OCT 2006
Volume 62, Issue 5, pages 1220–1227, December 2006
How to Cite
Timmins, G. S. and Deretic, V. (2006), Mechanisms of action of isoniazid. Molecular Microbiology, 62: 1220–1227. doi: 10.1111/j.1365-2958.2006.05467.x
- Issue published online: 24 OCT 2006
- Article first published online: 11 OCT 2006
- Accepted 2 October, 2006.
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.