Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topoisomerases are ubiquitous enzymes necessary for controlling the interlinking and twisting of DNA molecules. Among the four topoisomerases identified in eubacteria, two, DNA gyrase and topoisomerase IV have been exploited by nature and the pharmaceutical industry as antibacterial targets. Natural products that are inhibitors of one or both of these topoisomerases include the coumarin and cyclothialidine classes, which interfere with adenosine triphosphate hydrolysis, cinodine, flavones, and terpenoid derivatives. The plasmid-encoded bacterial peptides micron B17 and CcdB also inhibit DNA gyrase. The quinolones, a synthetic class of antibacterials that act on both DNA gyrase and topoisomerase IV have had the broadest clinical applications, however. Quinolone congeners differ in their relative potencies for DNA gyrase and topoisomerase IV Studies of an expanding set of resistant mutant enzymes and the crystal structure of the homologous enzyme in yeast have contributed to our understanding of interactions of these drugs with topoisomerase-DNA complexes and the ways in which mutations effect resistance.
 ...
PMID:Bacterial topoisomerases, anti-topoisomerases, and anti-topoisomerase resistance. 971 Jun 72

DNA gyrase is an essential topoisomerase that is found in all bacteria and is the target of potent antibiotics, such as the quinolones. By creating DNA lesions and inducing the bacterial SOS response, these drugs are not only highly cytotoxic but also mutagenic. Discovery and analysis of natural molecules with anti-gyrase activities, such as the CcdB or microcin B17 proteins, hold promise for understanding further topoisomerase reactions and for the design of new antibiotics.
 ...
PMID:Bacterial death by DNA gyrase poisoning. 971 15

Quinolones are potent antibacterial agents that specifically target bacterial DNA gyrase and topoisomerase IV. Widespread use of these agents has contributed to the rise of bacterial quinolone resistance. Previous studies have shown that quinolone resistance arises by mutations in chromosomal genes. Recently, a multiresistance plasmid was discovered that encodes transferable resistance to quinolones. We have cloned the plasmid-quinolone resistance gene, termed qnr, and found it in an integron-like environment upstream from qacE Delta 1 and sulI. The gene product Qnr was a 218-aa protein belonging to the pentapeptide repeat family and shared sequence homology with the immunity protein McbG, which is thought to protect DNA gyrase from the action of microcin B17. Qnr had pentapeptide repeat domains of 11 and 28 tandem copies, separated by a single glycine with a consensus sequence of A/C D/N L/F X X. Because the primary target of quinolones is DNA gyrase in Gram-negative strains, we tested the ability of Qnr to reverse the inhibition of gyrase activity by quinolones. Purified Qnr-His(6) protected Escherichia coli DNA gyrase from inhibition by ciprofloxacin. Gyrase protection was proportional to the concentration of Qnr-His(6) and inversely proportional to the concentration of ciprofloxacin. The protective activity of Qnr-His(6) was lost by boiling the protein and involved neither quinolone inactivation nor independent gyrase activity. Protection of topoisomerase IV, a secondary target of quinolone action in E. coli, was not evident. How Qnr protects DNA gyrase and the prevalence of this resistance mechanism in clinical isolates remains to be determined.
 ...
PMID:Mechanism of plasmid-mediated quinolone resistance. 1194 63

Microcin B17 (MccB17) is a peptide antibiotic produced by Escherichia coli strains carrying the pMccB17 plasmid. MccB17 is synthesized as a precursor containing an amino-terminal leader peptide that is cleaved during maturation. Maturation requires the product of the chromosomal tldE (pmbA) gene. Mature microcin is exported across the cytoplasmic membrane by a dedicated ABC transporter. In sensitive cells, MccB17 targets the essential topoisomerase II DNA gyrase. Independently, tldE as well as tldD mutants were isolated as being resistant to CcdB, another natural poison of gyrase encoded by the ccd poison-antidote system of plasmid F. This led to the idea that TldD and TldE could regulate gyrase function. We present in vivo evidence supporting the hypothesis that TldD and TldE have proteolytic activity. We show that in bacterial mutants devoid of either TldD or TldE activity, the MccB17 precursor accumulates and is not exported. Similarly, in the ccd system, we found that TldD and TldE are involved in CcdA and CcdA41 antidote degradation rather than being involved in the CcdB resistance mechanism. Interestingly, sequence database comparisons revealed that these two proteins have homologues in eubacteria and archaebacteria, suggesting a broader physiological role.
 ...
PMID:The highly conserved TldD and TldE proteins of Escherichia coli are involved in microcin B17 processing and in CcdA degradation. 1202 38

DNA gyrase, a type II topoisomerase, is the sole supercoiling activity in the cell and is essential for cell survival. There are two proteinaceous inhibitors of DNA gyrase that are plasmid-borne and ensure maintenance of the plasmids in bacterial populations. However, the physiological role of GyrI, an inhibitor of DNA gyrase encoded by the Escherichia coli genome, has been elusive. Previously, we have shown that GyrI imparts resistance against microcin B17 and CcdB. Here, we find that GyrI provided partial/limited protection against the quinolone class of gyrase inhibitors but had no effect on inhibitors that interfere with the ATPase activity of the enzyme. Moreover, GyrI negated the effect of alkylating agents, such as mitomycin C and N-methyl- N-nitro- N-nitrosoguanidine, that act independently of DNA gyrase. Hence, in vivo, GyrI appears to be involved in reducing DNA damage from many sources. In contrast, GyrI is not effective against lesions induced by ultraviolet radiation. Furthermore, the expression of GyrI does not significantly alter the topology of DNA. Thus, although isolated as an inhibitor of DNA gyrase, GyrI seems to have a broader role in vivo than previously envisaged.
 ...
PMID:Chromosomally encoded gyrase inhibitor GyrI protects Escherichia coli against DNA-damaging agents. 1368 98

Xanthomonas albilineans produces a family of polyketide-peptide compounds called albicidins which are highly potent antibiotics and phytotoxins as a result of their inhibition of prokaryotic DNA replication. Here we show that albicidin is a potent inhibitor of the supercoiling activity of bacterial and plant DNA gyrases, with 50% inhibitory concentrations (40 to 50 nM) less than those of most coumarins and quinolones. Albicidin blocks the religation of the cleaved DNA intermediate during the gyrase catalytic sequence and also inhibits the relaxation of supercoiled DNA by gyrase and topoisomerase IV. Unlike the coumarins, albicidin does not inhibit the ATPase activity of gyrase. In contrast to the quinolones, the albicidin concentration required to stabilize the gyrase cleavage complex increases 100-fold in the absence of ATP. The slow peptide poisons microcin B17 and CcdB also access ATP-dependent conformations of gyrase to block religation, but in contrast to albicidin, they do not inhibit supercoiling under routine assay conditions. Some mutations in gyrA, known to confer high-level resistance to quinolones or CcdB, confer low-level resistance or hypersensitivity to albicidin in Escherichia coli. Within the albicidin biosynthesis region in X. albilineans is a gene encoding a pentapeptide repeat protein designated AlbG that binds to E. coli DNA gyrase and that confers a sixfold increase in the level of resistance to albicidin in vitro and in vivo. These results demonstrate that DNA gyrase is the molecular target of albicidin and that X. albilineans encodes a gyrase-interacting protein for self-protection. The novel features of the gyrase-albicidin interaction indicate the potential for the development of new antibacterial drugs.
 ...
PMID:The phytotoxin albicidin is a novel inhibitor of DNA gyrase. 1707 89

Qnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2-pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA-targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes.
...
PMID:Protective effect of Qnr on agents other than quinolones that target DNA gyrase. 2623 81

The introduction of azole heterocycles into a peptide backbone is the principal step in the biosynthesis of numerous compounds with therapeutic potential. One of them is microcin B17, a bacterial topoisomerase inhibitor whose activity depends on the conversion of selected serine and cysteine residues of the precursor peptide to oxazoles and thiazoles by the McbBCD synthetase complex. Crystal structures of McbBCD reveal an octameric B4C2D2 complex with two bound substrate peptides. Each McbB dimer clamps the N-terminal recognition sequence, while the C-terminal heterocycle of the modified peptide is trapped in the active site of McbC. The McbD and McbC active sites are distant from each other, which necessitates alternate shuttling of the peptide substrate between them, while remaining tethered to the McbB dimer. An atomic-level view of the azole synthetase is a starting point for deeper understanding and control of biosynthesis of a large group of ribosomally synthesized natural products.
 ...
PMID:Architecture of Microcin B17 Synthetase: An Octameric Protein Complex Converting a Ribosomally Synthesized Peptide into a DNA Gyrase Poison. 3066 81