2006/10/24 by Graham S. Timmins, Vojo Deretić · 2 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Biochemistry #Biology #Cancer therapeutics and mechanisms #Enzyme #In vitro #Isoniazid #Mechanism of action #Mycobacterium research and diagnosis #NAD+ kinase #Nitric oxide #Nucleic acid #Phenothiazines and Benzothiazines Synthesis and Activities #Tuberculosis
paper · pdf · doi:10.1111/j.1365-2958.2006.05467.x
openalex publication_date 2006/10/24 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.