ArticleACS chemical biology2013
Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Pharmacological effect of quinazoline-2,4(1H,3H)-dione derivatives: a review.Molecular diversity · 2026Review
- A Comprehensive Review on Discovery, Development, the Chemistry of Quinolones, and Their Antimicrobial Resistance.Current topics in medicinal chemistry · 2026Review
- From Infection to Tumor: Exploring the Therapeutic Potential of Ciprofloxacin Derivatives as Anticancer Agents.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Gyrase and Topoisomerase IV: Recycling Old Targets for New Antibacterials to Combat Fluoroquinolone Resistance.ACS infectious diseases · 2024Review
- Target-Mediated Fluoroquinolone Resistance inACS infectious diseases · 2024Article
- Overcoming Microbiome-Acquired Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma.Biomedicines · 2024Review
- Synthesis and Antibacterial Evaluation of Ciprofloxacin Congeners with Spirocyclic Amine Periphery.International journal of molecular sciences · 2023Article
- Identification of an ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase.Bioorganic & medicinal chemistry · 2020Article
- Quinolone antibiotics.MedChemComm · 2019Review
- Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase.ACS infectious diseases · 2019Article
- Examining the Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase IIα and IIβ.ACS omega · 2019Article
- Design, Synthesis and Biological Evaluation of Ciprofloxacin- Peptide Conjugates as Anticancer Agents.Iranian journal of pharmaceutical research : IJPR · 2019Article
- Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase.Bioorganic & medicinal chemistry letters · 2018Article
- When antibiotics turn toxic.Nature · 2018Article
- Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site.International journal of molecular sciences · 2018Article
- Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities.Antibiotics (Basel, Switzerland) · 2017Review
- Recognition of DNA Supercoil Geometry by Mycobacterium tuberculosis Gyrase.Biochemistry · 2017Article
- Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance.Biochemistry · 2017Article
- Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones.Nucleic acids research · 2016Article
- The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity.Molecules (Basel, Switzerland) · 2016Review
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7 authors.
Funding
Abstract
Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. On the basis of our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα.
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