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.
Drlica
K
K
Public Health Research Institute, New York, New York 10016, USA. drlica@phri.nyu.edu
Zhao
X
X
D001419:Bacteria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004269:DNA, Bacterial / Q000378:metabolism; D004352:Drug Resistance, Microbial; D005798:Genes, Bacterial; D009369:Neoplasms / Q000188:drug therapy; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*
D004269:DNA, Bacterial; D015363:Quinolones; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II