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Media type:
E-Article
Title:
Mechanisms of action of isoniazid
Contributor:
Timmins, Graham S.;
Deretic, Vojo
Published:
Wiley, 2006
Published in:
Molecular Microbiology, 62 (2006) 5, Seite 1220-1227
Language:
English
DOI:
10.1111/j.1365-2958.2006.05467.x
ISSN:
0950-382X;
1365-2958
Origination:
Footnote:
Description:
<jats:title>Summary</jats:title><jats:p>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<jats:sup>+</jats:sup> and NADP<jats:sup>+</jats:sup> 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, <jats:italic>in vitro</jats:italic> biochemical studies and free radical chemistry – which is the intent of this review.</jats:p>