MECHANISMS OF QUINOLONE RESISTANCE

Two mechanisms of resistance to fluoroquinolones are known: (i) altera tion of the molecular target of quinolone action - DNA gyrase, and (ii ) reduction of the quinolone accumulation. Mutations altering the N-te rminus of the gyrase A subunit, especially those around residues Ser83 and Asp87, significantly reduce the susceptibilities towards all quin olones, while alterations of the gyrase B subunit are rarely found and are of minor importance. Reduced drug accumulation is associated with alterations of the outer membrane protein profile in gram-negative ba cteria. Such mutations include the marA locus in Escherichia call and result in low level resistance towards quinolones and unrelated drugs. Increased activity of naturally existing efflux systems, such as the transmembrane protein NorA of staphylococci, may also lead to reduced accumulation in gram-positive and gramnegative bacteria. Clinical fluo roquinolone resistance is rarely found in intrinsically highly suscept ible organisms such as Enterobacteriaceae and involves a combination o f at least two mutations. In contrast, species with moderate intrinsic susceptibility such as Campylobacter jejuni, Pseudomonas aeruginosa, and Staphylococcus aureus require only one mutation to become clinical ly resistant. As a consequence development of resistance during therap y may result from acquisition of already resistant strains in the case of susceptible species, and selection of mutants in the case of less susceptible species.