ArticleProceedings of the National Academy of Sciences of the United States of America2016
Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers.
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Who cites it
113 citing papers in PubMed, 218 citations in OpenAlex.
- Deep learning extracts MoA-specific signatures from high-throughput images of chemically and genetically perturbedScience advances · 2026Article
- Bidentate Metal-Binding Motifs in US FDA Approved Small Molecule Drugs.Journal of medicinal chemistry · 2026Review
- Two Novel 1,4-Naphthoquinone Derivatives as Potent Agents Against Multidrug-Resistant Staphylococcus aureus and Pathogenic Gram-Positive Bacteria.Drug development research · 2026Article
- AssessingbioRxiv : the preprint server for biology · 2026Article
- Bacterial type II topoisomerases cleave DNA in a species-specific manner.Nucleic acids research · 2026Article
- The Difluoroboranyl-Fluoroquinolone Derivative "7a" Inhibits Bacterial DNA Gyrase and Exhibits Potent Activity Against Ciprofloxacin-ResistantMolecules (Basel, Switzerland) · 2026Article
- Coordinated topoisomerase function shapes the fluoroquinolone response ofbioRxiv : the preprint server for biology · 2026Article
- Structural and Computational Analysis ofBiomolecules · 2026Article
- AI-guided competitive docking for virtual screening and compound efficacy prediction.npj drug discovery · 2026Article
- Structural modeling and docking analysis of canonical and novel resistance-associated missense mutations in Sudanese Escherichia coli.Scientific reports · 2026Article
- Spectrochemical, medicinal, and toxicological studies of moxifloxacin and its novel analogs: a quantum chemistry and drug discovery approach.RSC advances · 2026Article
- Synthesis, Biological Evaluation, and Molecular Docking of Tellurium-Containing Benzothiazole Derivatives as Enzyme Inhibitors of DNA Gyrase and Dihydrofolate Reductase.BioMed research international · 2026Article
- Fluoroquinolones as the linchpin of tuberculosis therapy: contrasting efficacy and resistance profiles inFrontiers in cellular and infection microbiology · 2026Article
- Structural and Computational Analysis ofbioRxiv : the preprint server for biology · 2025Article
- Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in M. tuberculosis clinical isolates.Tuberculosis (Edinburgh, Scotland) · 2025Article
- Structural interactions of BWC0977 with Klebsiella pneumoniae topoisomerase IV and biochemical basis of its broad-spectrum activity.Communications biology · 2025Article
- Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection inbioRxiv : the preprint server for biology · 2025Article
- Quinolone Resistance and Zoonotic Potential ofAntibiotics (Basel, Switzerland) · 2025Article
- Investigation of WQ-3810, a Fluoroquinolone with a High Potential Against Fluoroquinolone-ResistantAntibiotics (Basel, Switzerland) · 2025Article
- Structural Mechanisms of Topoisomerase-Targeting Drugs.Annual review of biochemistry · 2025Review
53 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are critical agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were determined in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resolution, show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a reduction in contacts to the water shell of an associated magnesium ion, which bridges fluoroquinolone-gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone-enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compounds that have increased potency against Mtb and the ability to overcome resistance.
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