Mode of Action of the Quinolone Antimicrobial Agents: Review of Recent Information

Recent studies concerning the mechanism of action of quinolones against DNA gyrase are reviewed. DNA gyrase is an essential bacterial enzyme known to be a primary target of quinolone agents. Quinolone-resistant alleles of both the gyrA and gyrB genes of DNA gyrase have been sequenced, and domains that affect the action of quinolones have been identified within the amino terminus of the gyrase A peptide and the midportion of the gyrase B peptide. In addition, an ATP-induced structural transition of DNA complexed with DNA gyrase was shown to be blocked by norfloxacin, but the means by which quinolones effect this change and the molecular site of quinolone binding remain unclear. Studies of structure-activity relationships of the quinolone molecule have been expanded and have included effects of quinolones on DNA gyrase. Stereochemical effects at positions 1 and 7 have been found. Substitutions at position 7 that improve potency against gram-positive bacteria have also been identified. Novel mono- and three-ring structures and an isothiazolo substitution at position 3 have broadened the range of structures known to have activity. Studies of bacterial killing by quinolones have revealed additional correlations with markers of DNA damage and additional alterations in bacteria and growth conditions that affect bacterial killing. The exact events responsible for quinolone-mediated lethality, however, remain undefined.