ArticleAntimicrobial agents and chemotherapy2007
Dual targeting of GyrB and ParE by a novel aminobenzimidazole class of antibacterial compounds.
Article in Antimicrobial agents and chemotherapy, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 90 citations in OpenAlex.
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- Revolutionizing tuberculosis treatment: Breakthroughs, challenges, and hope on the horizon.Acta pharmaceutica Sinica. B · 2025Review
- A Review of Antibacterial Candidates with New Modes of Action.ACS infectious diseases · 2024Review
- A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-ResistantAntimicrobial agents and chemotherapy · 2022Article
- In vitro activity of SPR719 against Mycobacterium ulcerans, Mycobacterium marinum and Mycobacterium chimaera.PLoS neglected tropical diseases · 2021Article
- Pipeline of anti-Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities.Medicinal research reviews · 2021Review
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- Synthesis and biological profile of substituted benzimidazoles.Chemistry Central journal · 2018Article
- Escherichia coli Topoisomerase IV E Subunit and an Inhibitor Binding Mode Revealed by NMR Spectroscopy.The Journal of biological chemistry · 2016Article
- Discovery of Pyrazolopyridones as a Novel Class of Gyrase B Inhibitors Using Structure Guided Design.ACS medicinal chemistry letters · 2016Article
- The Prodrug Approach: A Successful Tool for Improving Drug Solubility.Molecules (Basel, Switzerland) · 2015Review
- Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.ACS medicinal chemistry letters · 2015Article
- A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections.Antimicrobial agents and chemotherapy · 2015Article
- In vitro antibacterial activity of AZD0914, a new spiropyrimidinetrione DNA gyrase/topoisomerase inhibitor with potent activity against Gram-positive, fastidious Gram-Negative, and atypical bacteria.Antimicrobial agents and chemotherapy · 2015Article
- A novel high-throughput cell-based assay aimed at identifying inhibitors of DNA metabolism in bacteria.Antimicrobial agents and chemotherapy · 2014Article
- High in vitro activity of the novel spiropyrimidinetrione AZD0914, a DNA gyrase inhibitor, against multidrug-resistant Neisseria gonorrhoeae isolates suggests a new effective option for oral treatment of gonorrhea.Antimicrobial agents and chemotherapy · 2014Article
- Biological evaluation of benzothiazole ethyl urea inhibitors of bacterial type II topoisomerases.Antimicrobial agents and chemotherapy · 2013Article
- Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.PloS one · 2013Article
- Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis.The Journal of antimicrobial chemotherapy · 2012Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A structure-guided drug design approach was used to optimize a novel series of aminobenzimidazoles that inhibit the essential ATPase activities of bacterial DNA gyrase and topoisomerase IV and that show potent activities against a variety of bacterial pathogens. Two such compounds, VRT-125853 and VRT-752586, were characterized for their target specificities and preferences in bacteria. In metabolite incorporation assays, VRT-125853 inhibited both DNA and RNA synthesis but had little effect on protein synthesis. Both compounds inhibited the maintenance of negative supercoils in plasmid DNA in Escherichia coli at the MIC. Sequencing of DNA corresponding to the GyrB and ParE ATP-binding regions in VRT-125853- and VRT-752586-resistant mutants revealed that their primary target in Staphylococcus aureus and Haemophilus influenzae was GyrB, whereas in Streptococcus pneumoniae it was ParE. In Enterococcus faecalis, the primary target of VRT-125853 was ParE, whereas for VRT-752586 it was GyrB. DNA transformation experiments with H. influenzae and S. aureus proved that the mutations observed in gyrB resulted in decreased susceptibilities to both compounds. Novobiocin resistance-conferring mutations in S. aureus, H. influenzae, and S. pneumoniae were found in gyrB, and these mutants showed little or no cross-resistance to VRT-125853 or VRT-752586 and vice versa. Furthermore, gyrB and parE double mutations increased the MICs of VRT-125853 and VRT-752586 significantly, providing evidence of dual targeting. Spontaneous frequencies of resistance to VRT-752586 were below detectable levels (<5.2x10(-10)) for wild-type E. faecalis but were significantly elevated for strains containing single and double target-based mutations, demonstrating that dual targeting confers low levels of resistance emergence and the maintenance of susceptibility in vitro.
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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.