Mechanisms of Resistance to Quinolones

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Abstract
Mechanisms of resistance to the quinolones have been described for several bacterial species, but mainly for Escherichia coli and Staphylococcus aureus. Two principal mechanisms have been described: 1) alteration of the DNA gyrase, which is the target site of the quinolones; and 2) diminished accumulation in the cell as a result of either decreased uptake or increased efflux. Alteration of DNA gyrase is usually the result of a mutation in the gyrA, or more rarely, the gyrB gene. All substitutions in subunit A of the gyrase are located in the 67 to 106 amino-acid domain and are clustered around Ser-83 in E. coli and Ser-84 in S. aureus. A decrease in uptake has been described for Gram-negative bacteria such as Enterobacteriaceae and Pseudomonas aeruginosa. It has almost always been correlated with a modified electrophoretic profile of outer membrane proteins of the quinolone-resistant mutants. In E. coli, a decrease in OmpF seemed to be linked to the activation of the micF operon in most of the mutants described. These mutants were cross-resistant to unrelated antibiotics, such as trimethoprim, chloramphenicol, tetracycline, and some β-lactams. In all these mutants the normal or enhanced efflux of quinolones increased the level of resistance. Enhanced efflux has been described as the second mechanism of resistance in S. aureus. Acquired resistance to the quinolones was thought, until recently, to result from chromosomal mutation. Plasmid-mediated resistance associated with an enhanced efflux has been described in S. aureus, but this needs to be confirmed. When a high level of resistance is observed, 2 or 3 mechanisms may be involved. Alteration of DNA gyrase generally results in higher levels of quinolone resistance than decreased permeability or enhanced efflux in S. aureus. Appropriate quinolone therapy must be employed to minimise the selection of quinolone-resistant mutants and to prevent the spread of quinolone resistance among S. aureus, especially if the recent observation of plasmid-mediated resistance is confirmed.

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