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Mechanism of Binding of Fluoroquinolones to the Quinolone Resistance‐Determining Region of DNA Gyrase: Towards an Understanding of the Molecular Basis of Quinolone Resistance
Author(s) -
Madurga Sergio,
SánchezCéspedes Javier,
Belda Ignasi,
Vila Jordi,
Giralt Ernest
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200800041
Subject(s) - dna gyrase , quinolone , docking (animal) , ciprofloxacin , chemistry , ofloxacin , dna , binding site , moxifloxacin , levofloxacin , antibiotics , biochemistry , microbiology and biotechnology , biology , escherichia coli , gene , medicine , nursing
We have studied the bacterial resistance to fluoroquinolones that arises as a result of mutations in the DNA gyrase target protein. Although it is known that DNA gyrase is a target of quinolone antibacterial agents, the molecular details of the quinolone–gyrase interaction remain unclear. The mode of binding of ciprofloxacin, levofloxacin, and moxifloxacin to DNA gyrase was analyzed by means of docking calculations over the surface of the QRDR of GyrA. The analysis of these binding models allows study of the resistance mechanism associated with gyrA mutations more commonly found in E. coli fluoroquinolone‐resistant strains at the atomic level. Asp87 was found to be critical in the binding of these fluoroquinolones because it interacts with the positively charged nitrogens in these bactericidal drugs. The role of the other most common mutations at amino acid codon Ser83 can be explained through the contacts that the side chain of this residue establishes with fluoroquinolone molecules. Finally, our results strongly suggest that, although Arg121 has never been found to be associated with fluoroquinolone resistance, this residue makes a pivotal contribution to the binding of the antibiotic to GyrA and to defining its position in the QRDR of the enzyme.