Molecular Determinants of the Bacterial Resistance to Fluoroquinolones: A Computational Study
Cecylia S. Lupala,
Juan J. Perez.
Quinolones constitute a large class of antibacterial agents whose action is mediated through the formation of a
ternary complex with DNA and either, DNA Gyrase or topoisomerase IV, resulting in the inhibition of DNA replication.
In order to get a deeper insight into the features of the complex formation, we carried out docking studies of fifteen
diverse quinolones to the cleaved topoisomerase IV-DNA complex. Docking studies were performed using the crystal
structures of the cleaved complex with levofloxacin and moxifloxacin (pdb entries 3K9F and 2XKK, respectively) using
the GOLD software. Ligands dock in positions similar to those of the crystal structures. Analysis of the results reveals that
bound quinolones appear intercalated between the two nucleotides that are involved in the DNA cleavage and exhibit
hydrogen bonds with Arg117 and, the latter mediated though a water molecule. Arg117 has not been described to be
involved in resistance, since it is putatively involved in the enzymatic reaction and its mutation would be lethal for the
organism. Mutants of Ser79 exhibit resistance to quinolones which can be explained by the loss of an important anchoring
point. Interestingly, quinolone resistance observed in Asp83 mutants cannot be explained directly on the basis of the loss
of a direct interaction, but could be explained on the basis of its involvement at the entrance of the ligands to their binding
pocket since the residue is located at the mouth of the pocket. The results of the present study suggest that the 4-keto and
3-carboxyl groups of the fluoroquinolones bind a Mg2+ before binding to the cleaved topoisomarase IV-DNA complex
and use Asp83 for entry into the binding pocket. Accordingly, mutations that do not conserve the binding capacity for the
quinolone-Mg2+ complex will prevent the binding of this class of ligands. The results we present here are also compared
with the structure of PD0305970 a 2,4-dione active against the Ser79 and Asp83 mutants.
Keywords: Quinolones, topoisomerase IV, DNA gyrase, antibiotic resistance, antibiotics mode of action.
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