1. Dual Targets

Quinolones re known to interact with DNA gyrase and topoisomerase IV. Proofs regarding these are through studies made about mutations in E.coli and Staphylococcus aureus which reveals homology between the genes encoding its subunits. The primary drug target enzyme as defined by first-step resistance mutations thus often differs between a Gram-positive and Gram-negative bacteria.

For E.coli, purified DNA gyrase is more sensitive to many quinolones than purified topoisomerase IV, and, conversely, in S. aureus, purified topoisomerase IV is the more sensitive of the 2 enzymes. Therefore, the more sensitive enzyme generally determines the primary drug target thus determines cell susceptibility.

However, this does not hold true for some bacteria like S. pneumoniae.

For quinolones with different activities against the 2 target enzymes, potency and pharmacokinetic properties may also have effects on the likelihood of resistance.

It is  not yet clear if the action of quinolones in other species is similar to others. In Mycobacterium tuberculosis, H. pylori and Treponema pallidum, dual targeting is not possible because they lack genes for topoisomerase IV.

2. Consequences of quinolone interactions with target enzyme-DNA complex

Quinolones inhibit DNA synthesis and at higher concentrations inhibit RNA synthesis as well. This is  possible due to the their ability to stabilize complexes of DNA and type II topoisomerases. Complexes of  DNA, quinolone, and active topoisomerase IV appear to form physical barriers to DNA replication, but the DNA cleavage capability of topoisomerase IV is required.

In vivo, DNA synthesis inhibition by quinolone action with DNA gyrase occurs rapidly and this is due to its localization in on the bacterial chromosome. DNA gyrase is thought to be located in the in front of DNA replication forks so that collision occurs soon after quinolone-gyrase-DNA complexes form. This complex has also been shown to block the passage of RNA polymerase and to lead to premature termination of transcription.

3. Current models

Current models of fluoroquinolone action are based on collision of the replication complex with either DNA gyrase or topoisomerase IV with the resulting block to DNA synthesis. This will bring about the conversion of the complex to an irreversible state without generating overt DNA strand breaks.