Molecular determinants of the bacterial resistance to fluoroquinolones: a computational study
Abstract
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 Arg(117) and, the latter mediated though a water molecule. Arg(117) 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 Ser(79) exhibit resistance to quinolones which can be explained by the loss of an important anchoring point. Interestingly, quinolone resistance observed in Asp(83) 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.…
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