ArticleChemistry & biology2015
Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.
Article in Chemistry & biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 88 citations in OpenAlex.
- Article
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- Synthesis of Antimicrobial Quinoline Derivatives Enabled by Synergistic Pd/Enamine Catalysis: Experimental and Computational Study.Precision chemistry · 2026Article
- Identifying potent inhibitors for Mycobacterium tuberculosis MabA (FabG1).Molecular diversity · 2026Article
- Targeting opportunities presented by the pyrimidine biosynthesis pathway in Mycobacterium tuberculosis: a brief review.Biochemical Society transactions · 2026Review
- Key Proteins and Enzymatic Mechanisms Underlying Drug Resistance in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
- Uncovering Insights Into the Biology of Mycobacterium tuberculosis Using Genetic Tools.MicrobiologyOpen · 2025Review
- Evolutionarily divergent Mycobacterium tuberculosis CTP synthase filaments are under selective pressure.Nature communications · 2025Article
- Article
- Structural Basis of Bifunctional CTP/dCTP Synthase.Journal of molecular biology · 2024Article
- Architecture of CTPS filament networks revealed by cryo-electron tomography.Experimental cell research · 2024Article
- The Impact of Developmental and Metabolic Cues on Cytoophidium Formation.International journal of molecular sciences · 2024Review
- Article
- Polypharmacology-Driven Discovery and Design of Highly Selective, Dual and Multitargeting Inhibitors ofCurrent drug targets · 2024Review
- A metal-dependent conformational change provides a structural basis for the inhibition of CTP synthase by gemcitabine-5'-triphosphate.Protein science : a publication of the Protein Society · 2023Article
- Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: Hit-to-lead optimization and release of a novel antitubercular chemotype via scaffold derivatization.European journal of medicinal chemistry · 2023Article
- The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development.Molecular biomedicine · 2022Review
- Article
- Phenotypic drug discovery: recent successes, lessons learned and new directions.Nature reviews. Drug discovery · 2022Review
- CTP synthase: the hissing of the cellular serpent.Histochemistry and cell biology · 2022Review
Corrections and comments
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Authors and funding
29 authors at 10 institutions in 8 countries.
Funding
Abstract
To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.