ArticleThe Journal of biological chemistry2014
Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed.
- Coordinated topoisomerase function shapes the fluoroquinolone response ofMicrobiology spectrum · 2026Article
- Novel Bacterial Topoisomerase Inhibitors: A New Front in an Old War.Journal of molecular biology · 2026Review
- Antibiotic resistance mechanisms and global resistance patterns of Pseudomonas aeruginosa in microbial keratitis.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2026Review
- Silymarin conserves the efficacy of quinolone and sulfonamide in Nile tilapia (Oreochromis niloticus) subjected to aflatoxicosis and Streptococcus agalactiae infection.Scientific reports · 2026Article
- Characterization and targeting of deleterious mutations in Carbapenemase-producing Klebsiella pneumoniae: insights from variant calling, Computer-aided drug design, and DFT analysis.Archives of microbiology · 2026Article
- Unraveling the pathogenic potential, virulence traits, and antibiotic resistance genes of multidrug-resistant Streptococcus agalactiae strains retrieved from Nile tilapia.BMC microbiology · 2025Article
- Atmospheric Carbon Dioxide Modifies the Antimicrobial Activity and Oxidative Stress Generated by Ciprofloxacin inPathogens (Basel, Switzerland) · 2025Article
- Antechodynamics and Antechokinetics: Dynamics and Kinetics of Antibiotic Resistance Biomolecules.Biomolecules · 2025Review
- Quinolone scaffolds as potential drug candidates against infectious microbes: a review.Molecular diversity · 2025Review
- Suppression of amber stop codons impairs pathogenicity in Salmonella.FEBS letters · 2025Article
- Loss of SeqA confers low-level fluoroquinolone resistance through transcriptional reprogramming and RpoS dependence inAIMS microbiology · 2025Article
- Overexpression of the major facilitator superfamily efflux pump geneFrontiers in cellular and infection microbiology · 2025Article
- Article
- Structural basis of chiral wrap and T-segment capture byProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Antibacterial Mechanisms and Clinical Impact of Sitafloxacin.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Navigating fluoroquinolone resistance in Gram-negative bacteria: a comprehensive evaluation.JAC-antimicrobial resistance · 2024Review
- Resistome Signature and Antibiotic Resistance Mechanisms in Rhizospheric Soil Bacteriomes of Mecca Region, Saudi Arabia: Insights into Impact on Human Health.Life (Basel, Switzerland) · 2024Article
- Could traces of fluoroquinolones in food induce ciprofloxacin resistance inMicrobiology spectrum · 2024Article
- Novel fluoroquinolones analogues bearing 4-(arylcarbamoyl)benzyl: design, synthesis, and antibacterial evaluation.Molecular diversity · 2024Article
- Target-Mediated Fluoroquinolone Resistance inACS infectious diseases · 2024Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors.
Funding
Abstract
DNA gyrase and topoisomerase IV control bacterial DNA topology by breaking DNA, passing duplex DNA through the break, and then resealing the break. This process is subject to reversible corruption by fluoroquinolones, antibacterials that form drug-enzyme-DNA complexes in which the DNA is broken. The complexes, called cleaved complexes because of the presence of DNA breaks, have been crystallized and found to have the fluoroquinolone C-7 ring system facing the GyrB/ParE subunits. As expected from x-ray crystallography, a thiol-reactive, C-7-modified chloroacetyl derivative of ciprofloxacin (Cip-AcCl) formed cross-linked cleaved complexes with mutant GyrB-Cys(466) gyrase as evidenced by resistance to reversal by both EDTA and thermal treatments. Surprisingly, cross-linking was also readily seen with complexes formed by mutant GyrA-G81C gyrase, thereby revealing a novel drug-gyrase interaction not observed in crystal structures. The cross-link between fluoroquinolone and GyrA-G81C gyrase correlated with exceptional bacteriostatic activity for Cip-AcCl with a quinolone-resistant GyrA-G81C variant of Escherichia coli and its Mycobacterium smegmatis equivalent (GyrA-G89C). Cip-AcCl-mediated, irreversible inhibition of DNA replication provided further evidence for a GyrA-drug cross-link. Collectively these data establish the existence of interactions between the fluoroquinolone C-7 ring and both GyrA and GyrB. Because the GyrA-Gly(81) and GyrB-Glu(466) residues are far apart (17 Å) in the crystal structure of cleaved complexes, two modes of quinolone binding must exist. The presence of two binding modes raises the possibility that multiple quinolone-enzyme-DNA complexes can form, a discovery that opens new avenues for exploring and exploiting relationships between drug structure and activity with type II DNA topoisomerases.
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