Fluoroquinolones

FLUOROQUINOLONES

The fluoroquinolones selectively inhibit topoisomerases II and IV, which are not found in mammalian cells. The enzymes, both tetramers comprising two A and two B subunits, are capable of catalysing a variety of changes in DNA topology. The topoisomerases bind to the chromosome at points where two separate double-stranded regions cross. This can be at a supercoiled region, a knotted or a linked (catenane) region. The A subunits (gyrA for topoisomerase II and parC for topoisomerase IV) cut both DNA strands on one chain with a 4 base pair stagger; the other chain is passed through the break which is then resealed. The B subunits (gyrB for topoisomerase II and parE for topoisomerase IV) derive energy for the reaction by hydrolysis of ATP. The precise details of the interaction are not clear but it appears that the fluoroquinolones do not simply eliminate enzyme function, they actively poison the cells by trapping the topoisomerases as drug–enzyme–DNA complexes in which double-stranded DNA breaks are held together by the enzyme protein alone. The enzymes are unable to reseal the DNA, with the result that the chromosome in treated cells becomes fragmented. The number of fragments (approximately 100 per cell) is comparable to the number of supercoils in the chromosome. The action of the fluoroquinolones probably triggers secondary responses in the cells which are responsible for death. One notable morphological effect of fluoroquinolone treatment of Gram-negative rod-shaped organisms is the formation of filaments. In Gram-positive cocci topoisomerase IV may be the more important target for fluoroquinolone action.