Mechanisms of quinolone resistance.
Two mechanisms of resistance to fluoroquinolones are known: (i) alteration of the molecular target of quinolone action-DNA gyrase, and (ii) reduction of the quinolone accumulation. Mutations altering the N-terminus of the gyrase A subunit, especially those around residues Ser83 and Asp87, significantly reduce the susceptibilities towards all quinolones, 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 bacteria. Such mutations include the marA locus in Escherichia coli 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 gram-negative bacteria. Clinical fluoroquinolone resistance is rarely found in intrinsically highly susceptible organisms such as Enterobacteriaceae and involves a combination of 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 clinically resistant. As a consequence development of resistance during therapy 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.
Wiedemann
B
B
Pharmazeutische Mikrobiologie, Universität Bonn, Germany.
Heisig
P
P
D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001425:Bacterial Outer Membrane Proteins / Q000187:drug effects* / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004269:DNA, Bacterial / Q000235:genetics*; D004352:Drug Resistance, Microbial / Q000235:genetics*; D024841:Fluoroquinolones; D006090:Gram-Negative Bacteria; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology*; D006094:Gram-Positive Bacteria; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D014018:Tissue Distribution
D000890:Anti-Infective Agents; D001425:Bacterial Outer Membrane Proteins; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D004250:DNA Topoisomerases, Type II