The mode of action of quinolones involves interactions with both DNA gyrase, the originally recognised drug target, and topoisomerase IV, a related type II topoisomerase. In a given bacterium these 2 enzymes often differ in their relative sensitivities to many quinolones, and commonly DNA gyrase is more sensitive in gram-negative bacteria and topoisomerase IV more sensitive in gram-positive bacteria. Usually the more sensitive enzyme represents the primary drug target determined by genetic tests, but poorly understood exceptions have been documented. The formation of the ternary complex of quinolone, DNA, and either DNA gyrase or topoisomerase IV occurs through interactions in which quinolone binding appears to induce changes in both DNA and the topoisomerase that occur separately from the DNA cleavage that is the hallmark of quinolone action. X-ray crystallographic studies of a fragment of the gyrase A subunit, as well as of yeast topoisomerase IV, which has homology to the subunits of both DNA gyrase and topoisomerase IV, have revealed domains that are likely to constitute quinolone binding sites, but no topoisomerase crystal structures that include DNA and quinolone have been reported to date. Inhibition of DNA synthesis by quinolones requires the targeted topoisomerase to have DNA cleavage capability, and collisions of the replication fork with reversible quinolone-DNA-topoisomerase complexes convert them to an irreversible form. However, the molecular factors that subsequently generate DNA double-strand breaks from the irreversible complexes and that probably initiate cell death have yet to be defined.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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