Mode of action of the new quinolones: new data.

Abstract

New details of the molecular interactions of quinolones with their target DNA gyrase and DNA have come from the nucleotide sequences of the gyrA genes from resistant mutants of Escherichia coli and wild-type strains of other bacteria and studies of gyrase A tryptic fragments, all suggesting the importance of an amino-terminal domain in quinolone action. Alterations in DNA supertwisting were also associated with altered quinolone susceptibility, possibly by indirect effects on DNA gyrase expression. Specific binding of relevant concentrations of norfloxacin to a complex of DNA gyrase and DNA in the presence of ATP, the cooperativity of DNA binding, and the crystalline structure of nalidixic acid have led to a model in which quinolones bind cooperatively to a pocket of single-strand DNA created by DNA gyrase. Quinolones vary in their relative activity against DNA gyrase and its eukaryotic homolog topoisomerase II, and in some assays increased action against the eukaryotic enzyme was associated with genotoxicity. Inhibition of bacterial DNA synthesis by quinolones may correlate with MICs in some species, but comparisons of drug accumulation and inhibition of DNA synthesis in permeabilized cells among species have been difficult to interpret. The specific factors necessary for bacterial killing by quinolones in addition to interaction with DNA gyrase have remained elusive, but include oxygen and new protein synthesis. The coordinate expression of the SOS proteins appears not to be necessary for quinolone lethality. Two independent mutants with selective reduced killing by quinolones and beta-lactams indicate overlap in the pathways of bactericidal activity of these classes of agents with distinct targets.