ArticleAntimicrobial agents and chemotherapy2010
Mycobacterium tuberculosis dihydrofolate reductase is not a target relevant to the antitubercular activity of isoniazid.
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39 citing papers in PubMed, 71 citations in OpenAlex.
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- Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement.Frontiers in pharmacology · 2024Review
- Structural and Biochemical Characterization ofBiomolecules · 2023Article
- Structural Elements Involved in ATP Hydrolysis Inhibition and ATP Synthesis of Tuberculosis and Nontuberculous Mycobacterial F-ATP Synthase Decipher New Targets for Inhibitors.Antimicrobial agents and chemotherapy · 2022Article
- Tools to Alleviate the Drug Resistance inMolecules (Basel, Switzerland) · 2022Review
- Article
- The pMy vector series: A versatile cloning platform for the recombinant production of mycobacterial proteins in Mycobacterium smegmatis.Protein science : a publication of the Protein Society · 2020Article
- Allosteric regulation of menaquinone (vitamin KThe Journal of biological chemistry · 2020Article
- A revised biosynthetic pathway for the cofactor FNature communications · 2019Article
- Drug-Resistant Tuberculosis, Lebanon, 2016 - 2017.Emerging infectious diseases · 2019Article
- Dormant Mycobacterium tuberculosis converts isoniazid to the active drug in a Wayne's model of dormancy.The Journal of antibiotics · 2018Article
- A GFP-strategy for efficient recombinant protein overexpression and purification inRSC advances · 2018Article
- Structural and functional determination of homologs of theThe Journal of biological chemistry · 2018Article
- Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Frontiers in cellular and infection microbiology · 2018Review
- Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice.Clinical and vaccine immunology : CVI · 2017Article
- Diverse drug-resistant subpopulations of Mycobacterium tuberculosis are sustained in continuous culture.Journal of the Royal Society, Interface · 2016Article
- Elongation of the Poly-γ-glutamate Tail of F420 Requires Both Domains of the F420:γ-Glutamyl Ligase (FbiB) of Mycobacterium tuberculosis.The Journal of biological chemistry · 2016Article
- The Chromosomal parDE2 Toxin-Antitoxin System of Mycobacterium tuberculosis H37Rv: Genetic and Functional Characterization.Frontiers in microbiology · 2016Article
- Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315.PloS one · 2015Article
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12 authors at 4 institutions in 1 country.
Funding
Abstract
Mycobacterium tuberculosis enoyl-acyl-ACP reductase (InhA) has been demonstrated to be the primary target of isoniazid (INH). Recently, it was postulated that M. tuberculosis dihydrofolate reductase (DHFR) is also a target of INH, based on the findings that a 4R-INH-NADP adduct synthesized from INH by a nonenzymatic approach showed strong inhibition of DHFR in vitro, and overexpression of M. tuberculosis dfrA in M. smegmatis conferred a 2-fold increase of resistance to INH. In the present study, a plasmid expressing M. tuberculosis dfrA was transformed into M. smegmatis and M. tuberculosis strains, respectively. The transformant strains were tested for their resistance to INH. Compared to the wild-type strains, overexpression of dfrA in M. smegmatis and M. tuberculosis did not confer any resistance to INH based on the MIC values. Similar negative results were obtained with 14 other overexpressed proteins that have been proposed to bind some form of INH-NAD(P) adduct. An Escherichia coli cell-based system was designed that allowed coexpression of both M. tuberculosis katG and dfrA genes in the presence of INH. The DHFR protein isolated from the experimental sample was not found bound with any INH-NADP adduct by enzyme inhibition assay and mass spectroscopic analysis. We also used whole-genome sequencing to determine whether polymorphisms in dfrA could be detected in six INH-resistant clinical isolates known to lack mutations in inhA and katG, but no such mutations were found. The dfrA overexpression experiments, together with the biochemical and sequencing studies, conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH.
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