DNA GYRASE, TOPOISOMERASE-IV, AND THE 4-QUINOLONES

For many years, DNA gyrase was thought to be responsible both for unli nking replicated daughter chromosomes and for controlling negative sup erhelical tension in bacterial DNA. However, in 1990 a homolog of gyra se, topoisomerase IV, that had a potent decatenating activity was disc overed. It is now clear that topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, top oisomerase IV is a target of the 4-quinolones, antibacterial agents th at had previously been thought to target only gyrase. The key event in quinolone action is reversible trapping of gyrase-DNA and topoisomera se IV-DNA complexes. Complex formation with gyrase is followed by a ra pid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell dea th occurs as double-strand DNA breaks are released from trapped gyrase and/or topoisomerase IV complexes. Repair of quinolone-induced DNA da mage occurs largely via recombination pathways. In many gram-negative bacteria resistance to moderate levels of quinolone arises from mutati on 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 re sistance occurs through changes in topoisomerase IV while gyrase chang es give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quino lone-topoisomerase biology is providing a model for understanding aspe cts of host-parasite interactions and providing ways to investigate ma nipulation of the bacterial chromosome by topoisomerases.