Fluoroquinolones: mechanisms of action and resistance

The mechanism of action and the mechanism of resistance of the 4-quinolones are complex and poorly understood. The first barrier these molecules must cross is the bacterial outer membrane. In gram-negative species, 4-quinolones pass through either the porins or lipopolysaccharides (or both) depending on their chemical nature. The cellular target is the DNA of the bacterial chromosome. 4-Quinolones mainly modify the activity of topoisomerase II or DNA gyrase, but also that of topoisomerase I and IV. Any damage to the bacterial genome will induce a stress response which consists in the SOS response, chaperonin synthesis or the generation of oxygen free radicals. Peptidoglycan synthesis is also modified, as shown by the inhibition of PBP(3) activity. Mechanism of resistance involves mutations on gyrA and gyrB genes. gyrA Mutations on the chromosome are responsible for a high level of resistance due to a modification of the A subunit of DNA gyrase, mutations on gyrB gene are responsible for a low level of resistance; the combination of both mutations leads to a high level of resistance. Other mutations are responsible for increasing the MIC, such as a norA mutation in S. aureus. The antibacterial activity of the various molecules is different and, as a result, there is not a single mechanism of action or resistance, but rather a common trunk on which additional mechanisms are grafted.