ArticleAntimicrobial agents and chemotherapy2015
Targeting Mycobacterium tuberculosis topoisomerase I by small-molecule inhibitors.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 63 citations in OpenAlex.
- Search for Specific Inhibitors Targeting Type IA Topoisomerases.Journal of molecular biology · 2026Review
- Inhibition of DNA cleavage and strand passage activities of Mycobacterium tuberculosis topoisomerase I.Nucleic acids research · 2025Article
- Evaluation of Amlodipine and Imipramine Efficacy to TreatAntibiotics (Basel, Switzerland) · 2025Article
- Small Molecule Inhibitors ofInternational journal of molecular sciences · 2024Article
- Blunted blades: new CRISPR-derived technologies to dissect microbial multi-drug resistance and biofilm formation.mSphere · 2024Review
- Review
- Article
- Target Identification in Anti-Tuberculosis Drug Discovery.International journal of molecular sciences · 2023Review
- Unraveling topoisomerase IA gate dynamics in presence of PPEF and its preclinical evaluation against multidrug-resistant pathogens.Communications biology · 2023Article
- Implementation of a mycobacterial CRISPRi platform in Mycobacterium abscessus and demonstration of the essentiality of ftsZTuberculosis (Edinburgh, Scotland) · 2023Article
- FDA-Approved Amoxapine Effectively Promotes Macrophage Control of Mycobacteria by Inducing Autophagy.Microbiology spectrum · 2022Article
- Article
- A tale of topoisomerases and the knotty genetic material in the backdrop of Plasmodium biology.Bioscience reports · 2022Review
- Chrysomycin A inhibits the topoisomerase I of Mycobacterium tuberculosis.The Journal of antibiotics · 2022Article
- Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to Mycobacterium tuberculosis infection.The Journal of antimicrobial chemotherapy · 2022Article
- DNA-Dependent Binding of Nargenicin to DnaE1 Inhibits Replication inACS infectious diseases · 2022Article
- Localization ofFrontiers in microbiology · 2022Article
- Type IA Topoisomerases as Targets for Infectious Disease Treatments.Microorganisms · 2021Review
- Various Facets of Pathogenic Lipids in Infectious Diseases: Exploring Virulent Lipid-Host Interactome and Their Druggability.The Journal of membrane biology · 2020Review
- Targeting Genome Integrity inMolecules (Basel, Switzerland) · 2020Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and M. tuberculosis cells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison the M. tuberculosis and M. smegmatis topoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules.
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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.