DNA gyrase, topoisomerase IV, and the 4-quinolones.
Article Details
- CitationCopy to clipboard
Drlica K, Zhao X
DNA gyrase, topoisomerase IV, and the 4-quinolones.
Microbiol Mol Biol Rev. 1997 Sep;61(3):377-92.
- PubMed ID
- 9293187 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Cinoxacin DNA gyrase subunit A Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Ciprofloxacin DNA topoisomerase 4 subunit A Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Fleroxacin DNA topoisomerase 4 subunit A Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Norfloxacin DNA gyrase subunit A Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Norfloxacin DNA topoisomerase 4 subunit A Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Ofloxacin DNA topoisomerase 4 subunit A Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Pefloxacin DNA gyrase subunit A Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails