Mechanisms of resistance to the 4-quinolone antibacterial agents

Because of the close structural relationship of the fluorinated 4-quinolones to the parent compound nalidixic acid the mechanism of resistance is often perceived to be the same. However, it is clear that whilst the mechanism of resistance to fluorinated 4-quinolones is essentially the same, strains that are selected as resistant to nalidixic acid generally retain sensitivity to the newer agents. A number of mutations in the chromosome of Escherichia coli have been identified and these are described. These mutations affect the interaction of quinolones with their presumed targets (DNA gyrases) and the transport of quinolones through the cell membrane. A small number of other mutations giving rise to low-level resistance to nalidixic acid, which affect neither gyrase nor membrane function, are also recognized. Despite the recognition of these mutations, the practical application of this information is hampered by lack of knowledge of the normal uptake mechanisms, the processes involved in selection and maintenance of resistance, the relationship of resistance to pathogenicity and the frequency of occurrence of these mutations.