Mechanisms of action of isoniazid

Molecular Microbiology - Tập 62 Số 5 - Trang 1220-1227 - 2006
Graham S. Timmins1, Vojo Deretić2,3
1College of Pharmacy
2Department of Cell Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
3Department of Molecular Genetics and Microbiology and

Tóm tắt

SummaryFor 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.

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Molecular Microbiology

Tập 62 Số 5

1220-1227

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