Mode of action of the quinolone antimicrobial agents.

The newer quinolone antimicrobial agents are more potent antibacterial agents than is the older analog nalidixic acid. For many of the quinolone agents, increased antibacterial potency correlates with increased potency in inhibiting the essential bacterial enzyme DNA gyrase. Studies with mutants resistant to drug action have identified the A subunit of this enzyme as a drug target. Other drug-resistance mutations are associated with pleiotropic drug resistance and decreased amounts of porin outer-membrane proteins and appear to involve alterations in permeability of the bacterium to the drug. Structure-activity studies of a large number of quinolone analogs have identified the importance to drug action of substituents at positions 1, 3, 4, 6, and 7 of the quinolone ring. Uncertainties remain, however, about the details of the molecular interactions of quinolones, DNA gyrase, and DNA and about the specific events that lead to quinolone-mediated bacterial killing.