Mechanisms of action of isoniazid

  title={Mechanisms of action of isoniazid},
  author={Graham S Timmins and Vojo Deretic},
  journal={Molecular Microbiology},
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… 
Synthesis, oxidation potential and anti–mycobacterial activity of isoniazid and analogues: insights into the molecular isoniazid activation mechanism
An activation mechanism for INH and analogues is proposed based on a one-electron oxidation step of the hydrazyl function at the proximal nitrogen followed by a radical transposition to the distal nitrogen, which then induces a b-homolytic cleavage of the C(=O)-N bond to afford diazene and the isonicotinoyl radical species.
Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action
Isoniazid eradicates latent tuberculosis (TB) by prompting slow differentiation of pro‐inflammatory monocytes and providing protection against reactive species‐induced “self‐necrosis” of phagocytes and suggests that the antibacterial properties of INH do not rely on KatG of Mtb.
Isoniazid with Multiple Mode of Action on Various MycobacterialEnzymes Resulting in Drug Resistance
The purpose of this review is to present the various mechanisms of action of isoniazid at different enzymes of MTB causing drug resistance.
Insights on the Mechanism of Action of INH-C10 as an Antitubercular Prodrug.
It is proposed that INH-C10 is able to exhibit better minimum inhibitory concentration values against certain variants because of its better ability to permeate through the lipid membrane, enhancing its availability inside the cell.
Acetylation of isoniazid - a novel mechanism of isoniazid resistance in Mycobacterium tuberculosis
The results strongly indicate that Rv2170 acetylates INH, and this could be one of the strategies adopted by at least some M. tuberculosis strains to overcome INH toxicity.
Update of Antitubercular Prodrugs from a Molecular Perspective: Mechanisms of Action, Bioactivation Pathways, and Associated Resistance
Identification of the prodrugs targets and a better understanding of their modes of action and also of their activation mechanisms are of crucial importance, as well as the reported resistance related to these mechanisms of activation/action.
Isoniazid: Radical-induced oxidation and reduction chemistry.
Acetylation of Isoniazid Is a Novel Mechanism of Isoniazid Resistance in Mycobacterium tuberculosis
Results strongly indicate that Rv2170 acetylates INH, and this could be one of the strategies adopted by at least some M. tuberculosis strains to overcome INH toxicity, although this needs to be tested in INH-resistant clinical strains.
Mechanisms of isoniazid‐induced idiosyncratic liver injury: Emerging role of mitochondrial stress
This review discusses these emerging new paradigms of INH‐induced DILI and highlights recent insights into the mechanisms, as well as points to the existing large gaps in the understanding of the pathogenesis.


Studies on the Mechanism of Action of Isoniazid and Ethionamide in the Chemotherapy of Tuberculosis
The inactivation of the enoyl-reductase InhA from Mycobacterium tuberculosis by reactive intermediates formed during the oxidn. of isoniazid and ethionamide was studied. Both drugs can generate
Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid
Using specialized linkage transduction, a single point mutation allele (S94A) within the putative target gene inhA was transferred in Mycobacterium tuberculosis and was sufficient to confer clinically relevant levels of resistance to isoniazid killing and inhibition of mycolic acid biosynthesis.
Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis.
Data from x-ray crystallography and mass spectrometry reveal that the mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the Nicotinamide ring of nicotinamide adenine dinucleotide bound within the active site of Inh A.
inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis.
Results suggest that InhA is likely a primary target of action for INH and ETH and that it may be involved in mycolic acid biosynthesis.
Evidence for the generation of active oxygen by isoniazid treatment of extracts of Mycobacterium tuberculosis H37Ra
Crude extracts of Mycobacterium tuberculosis H37Ra, an isonicotinic acid hydrazide (isoniazid) (INH)-susceptible strain which has peroxidase activity, catalyzed the production of catechol from phenol
Requirements for Nitric Oxide Generation from Isoniazid Activation In Vitro and Inhibition of Mycobacterial Respiration In Vivo
Investigation of the requirements and the pathway of nitric oxide generation during oxidative activation of INH by Mycobacterium tuberculosis KatG in vitro and in vivo provides in vivo evidence that INH-derived NO* can inhibit key mycob bacterial respiratory enzymes, which may contribute to the overall antimycobacterial action of InH.
Molecular basis for the exquisite sensitivity of Mycobacterium tuberculosis to isoniazid.
It is suggested that AhpC counteracts the action of INH and that the levels of its expression may govern the intrinsic susceptibility of mycobacteria to this front-line antituberculosis drug.
Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid
This work shows that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis in Mycobacterium tuberculosis, the first new target for isoniaZid identified in the last decade.
A review of the action of isoniazid.
  • J. Youatt
  • Medicine, Biology
    The American review of respiratory disease
  • 1969
It is suggested that the primary and specific action of isoniazid is to combine with an enzyme that is peculiar to the drug-susceptible strains of Mycobacterium tuberculosis, at the same time displacing a molecule that gives rise to pigment in conditions in which the drug is not lethal.
Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria*
In vitro assays demonstrated that KatG-activated INH, triclosan, and diazaborine inhibited InhA but not KasA activity, consistent with inhA being the primary target of INH.