DNA gyrase, topoisomerase IV, and the 4-quinolones

For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in Bacterial DNA. However, in 1990 a homolog of gyrase, Topoisomerase IV, that had a potent decatenating activity was discovered. It is now clear that Topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, Topoisomerase IV is a target of the 4-quinolones, Antibacterial agents that had previously been thought to target only gyrase. The key event in Quinolone action is reversible trapping of gyrase-DNA and Topoisomerase IV-DNA complexes. Complex formation with gyrase is followed by a rapid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell death occurs as double-strand DNA breaks are released from trapped gyrase and/or Topoisomerase IV complexes. Repair of quinolone-induced DNA damage occurs largely via recombination pathways. In many gram-negative bacteria, resistance to moderate levels of Quinolone arises from mutation of the gyrase A protein and resistance to high levels of Quinolone arises from mutation of a second gyrase and/or Topoisomerase IV site. For some gram-positive bacteria, the situation is reversed: primary resistance occurs through changes in Topoisomerase IV while gyrase changes give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the Bacterial chromosome by topoisomerases.