Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four drugs known to interact with topoisomerase II were assessed for their ability to enhance the cytotoxicity of cis-diamminedichloroplatinum(II) (CDDP) in Chinese hamster ovary (CHO) cell lines sensitive and resistant to VM-26. The combination treatments were analyzed by isobologram methodology. On 24 h exposure, there was no significant difference in the cytotoxicity of novobiocin or ciprofloxacin toward either cell line. The resistant cells were approximately 9-fold more resistant to 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and approximately 170-fold more resistant to etoposide after a 24-h exposure. The combination of novobiocin and cisplatin produced greater than additive cell kill over the entire dose range of cisplatin tested in both cell lines. m-AMSA and CDDP produced cell kill that fell within the envelope of additivity. Etoposide and CDDP resulted in cytotoxicity that was slightly greater than additive at low CDDP concentrations and additive at the highest concentration of CDDP tested in the parental cell line and was slightly greater than additive in the resistant cell line. Ciprofloxacin and CDDP, like novobiocin, resulted in greater than additive cell kill in both cell lines. The enhancement of CDDP cytotoxicity by novobiocin that was seen in exponentially growing cells was lost in stationary-phase cultures. In these studies, novobiocin and, to a lesser degree, ciprofloxacin produced greater than additive cell kill in combination with CDDP in parental and epipodophyllotoxin-resistant CHO cells.
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PMID:Ability of four potential topoisomerase II inhibitors to enhance the cytotoxicity of cis-diamminedichloroplatinum (II) in Chinese hamster ovary cells and in an epipodophyllotoxin-resistant subline. 217 96

1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazin-1- ylquinoline-3-carboxylic acid (ciprofloxacin, Bay o 9867, Ciprobay) is a broad spectrum antibiotic of the 4-quinolone group. It possesses a bactericidal effect attributable to the property of DNA-gyrase inhibition. The antimicrobial action comprises all grampositive strains (including Streptococcus faecalis) and gramnegative strains (including Pseudomonas aeruginosa and Serratia spp.), as well as Bacteroides fragilis and other Bacteroides species. In this comparative study the antimicrobial effect of ciprofloxacin was tested against 665 gramnegative, 412 grampositive and 274 anaerobic strains from fresh clinical isolates and compared with that of other frequently used antibiotics. The minimum inhibitory concentrations (MIC) were determined by means of a serial dilution test with micro standard plates. Within the group of gramnegative strains, ciprofloxacin was the most active antibiotic with an MIC90 of 0.12 mg/l to 0.5 mg/l for most isolates. Ciprofloxacin shows a broad spectrum of activity against gramnegative pathogenic bacteria including Escherichia coli, Klebsiella spp., Citrobacter spp., Enterobacter spp., Serratia spp. and Acinetobacter spp., and also covers resistant strains of Pseudomonas aeruginosa and Alcaligenes faecalis. Ciprofloxacin also shows a high inhibiting activity against grampositive strains (Staphylococci, Enterococci) and anaerobic pathogens.
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PMID:Comparative in vitro activity of ciprofloxacin against aerobic and anaerobic bacteria from clinical isolates. 282 54

The minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations of ciprofloxacin were compared with those of the cephalosporins HR 810 and cefotaxime in 250 strains from 10 species of Gram-negative bacteria with sensitivity or resistance to gentamicin and/or piperacillin. Ciprofloxacin had an inhibitory activity higher than, or practically equal to the best of the two cephalosporins. The MBC of ciprofloxacin was more often less than or equal to twice the MIC than with the beta-lactam antibiotics. Parallel resistance was found with pipemidic acid as representative of DNA-gyrase inhibitors. No direct parallel resistance was observed with resistance to gentamicin, piperacillin or cefotaxime.
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PMID:Comparative determination of minimal inhibitory and bactericidal concentrations of ciprofloxacin, cefotaxime and HR 810 for gram-negative bacteria either sensitive or resistant to ureidopenicillins and/or gentamicin. 293 27

Ciprofloxacin (CF), a fluoroquinolone widely used as a potent antimicrobial drug, was evaluated in vivo in mouse bone marrow cells for its ability to induce clastogenicity and DNA damage in terms of increased sister-chromatid exchange (SCE) frequencies. Doses of 0.6, 6 and 20 mg/kg body weight of CF given intraperitoneally induced a positive dose-dependent significant clastogenicity (trend test alpha < or = 0.05), though the effects were not specific for specific phases of the cell cycle. The DNA-damaging effect observed as increased SCE frequencies using doses of 0.15, 0.30, 0.60, 1.2 and 6 mg/kg body weight showed a significant dose-dependent increase (trend test alpha < or = 0.05; lowest effective concentration 1.2 mg/kg of body weight). Compared to a potent eukaryotic DNA topoisomerase type II poison, etoposide (VP-16, 0.5, 1 and 5 mg/kg body weight, given intraperitoneally), ciprofloxacin produced comparable dose-dependent SCE frequency increases. Ciprofloxacin was postulated to be specific for the target DNA gyrase, the prokaryotic homologue of DNA topoisomerase type II enzyme. The present paper along with the existing earlier data strongly suggest that topoisomerase type II and DNA gyrase are physiological targets for the drug action. In view of the present significant in vivo mammalian DNA topoisomerase type II-mediated genotoxicity and clastogenicity data, ciprofloxacin should be administered with caution.
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PMID:Ciprofloxacin: mammalian DNA topoisomerase type II poison in vivo. 767 75

DNA gyrase, the bacterial enzyme that supercoils DNA, is trapped on chromosomal DNA by the 4-quinolone compounds, as drug-gyrase complexes that contain DNA breaks. Examination of chromosomal DNA extracted from Escherichia coli indicated that bacteriostatic concentrations of oxolinic acid trap gyrase and block DNA synthesis without releasing broken DNA from gyrase-DNA complexes. Release, detected as free rotation of DNA in the presence of an intercalating dye, occurred only at high, bactericidal oxolinic acid concentrations. Release of DNA breaks and cell death were both blocked by chloramphenicol, an inhibitor of protein synthesis, suggesting that synthesis of additional protein activity is required to free the DNA ends. Ciprofloxacin, a more potent quinolone, released DNA breaks and killed cells even in the presence of chloramphenicol. It is proposed that this second, chloramphenicol-insensitive mode for release of DNA breaks and cell killing arises from dissociation of gyrase subunits. Ciprofloxacin also killed a gyrase (gyrA) mutant resistant to the prototype of quinolone, nalidixic acid, and created complexes on DNA detected by DNA fragmentation. This lethal effect of ciprofloxacin was eliminated by additional mutations mapping in parC, one of the two genes encoding topoisomerase IV. Thus, the fluoroquinolone compounds have two intracellular targets. In the absence of the gyrA mutation, the parC (CipR) allele did not by itself confer resistance to ciprofloxacin, indicating that gyrase is the major quinolone target in E. coli. These findings provide a molecular explanation for quinolone action in bacteria and a new way to study topoisomerase IV-chromosome interactions.
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PMID:DNA gyrase and topoisomerase IV on the bacterial chromosome: quinolone-induced DNA cleavage. 863 97

Many members of the Halobacteriaceae are inhibited by quinolone compounds, which inhibit type II DNA topoisomerase. Ciprofloxacin was the most potent inhibitor, followed by ofloxacin and norfloxacin. Ciprofloxacin concentration between 25 and 60 micrograms/ml caused 50% inhibition of the growth of most Haloferax and Haloarcula species. Halobacterium species were less sensitive, At sublethal concentrations, formation of elongated and/or swollen cells was observed in many species. The alkaliphilic Natronobacterium pharaonis was very sensitive (50% inhibition by ciprofloxacin, ofloxacin, and norfloxacin at concentrations between 4 and 15 micrograms/ml). The resistance of many members of the Halobacteriaceae to high concentrations of quinolone compounds may in part be due to the high magnesium concentrations present in the growth media. Haloferax volcanii was sensitive to 40 micrograms/ml ciprofloxacin when grown at suboptimal magnesium concentrations (0.1 M), but was hardly affected by 100 micrograms/ml of the inhibitor when grown in the presence of 0.5-0.75 M MgCl2. It is suggested that the putative archaeal type II DNA topoisomerase has properties similar to those of the enzyme from Bacteria, although its sensitivity to quinolone antimicrobial compounds may be lower.
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PMID:Sensitivity of selected members of the family Halobacteriaceae to quinolone antimicrobial compounds. 866 28

The genes encoding the ParC and ParE subunits of topoisomerase IV of Streptococcus pneumoniae, together with the region encoding amino acids 46 to 172 (residue numbers are as in Escherichia coli) of the pneumococcal GyrA subunit, were partially characterized. The gyrA gene maps to a physical location distant from the gyrB and parC loci on the chromosome, whereas parC is closely linked to parE. Ciprofloxacin-resistant (Cpr) clinical isolates of S. pneumoniae had mutations affecting amino acid residues of the quinolone resistance-determining region of ParC (low-level Cpr) or in both quinolone resistance-determining regions of ParC and GyrA (high-level Cpr). Mutations were found in residue positions equivalent to the serine at position 83 and the aspartic acid at position 87 of the E. coli GyrA subunit. Transformation experiments suggest that ParC is the primary target of ciprofloxacin. Mutation in parC appears to be a prerequisite before mutations in gyrA can influence resistance levels.
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PMID:ParC subunit of DNA topoisomerase IV of Streptococcus pneumoniae is a primary target of fluoroquinolones and cooperates with DNA gyrase A subunit in forming resistance phenotype. 889 Nov 24

Ciprofloxacin-resistant mutants of Streptococcus pneumoniae 7785 were generated by stepwise selection at increasing drug concentrations. Sequence analysis of PCR products from the strains was used to examine the quinolone resistance-determining regions of the GyrA and GyrB proteins of DNA gyrase and the analogous regions of the ParC and ParE subunits of DNA topoisomerase IV. First-step mutants exhibiting low-level resistance had no detectable changes in their topoisomerase quinolone resistance-determining regions, suggesting altered permeation or another novel resistance mechanism. Nine of 10 second-step mutants exhibited an alteration in ParC at Ser-79 to Tyr or Phe or at Ala-84 to Thr. Third- and fourth-step mutants displaying high-level ciprofloxacin resistance were found to have, in addition to the ParC alteration, a change in GyrA at residues equivalent to Escherichia coli GyrA resistance hot spots Ser-83 and Asp-87 or in GyrB at Asp-435 to Asn, equivalent to E. coli Asp-426, part of a highly conserved EGDSA motif in GyrB. No ParE changes were observed. Complementary analysis of two S. pneumoniae clinical isolates displaying low-level resistance to ciprofloxacin revealed a ParC change at Ser-79 to Phe or Arg-95 to Cys but no changes in GyrA, GyrB, or ParE. A highly resistant isolate, in addition to a ParC mutation, had a GyrA alteration at the residue equivalent to E. coli Asp-87. Thus, in both laboratory strains and clinical isolates, ParC mutations preceded those in GyrA, suggesting that topoisomerase IV is a primary topoisomerase target and gyrase is a secondary target for ciprofloxacin in S. pneumoniae.
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PMID:Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. 889 Nov 38

Topoisomerase II is the cytotoxic target for a number of clinically relevant antineoplastic drugs. Despite the fact that these agents differ significantly in structure, a previous study [Corbett, A. H., Hong, D., & Osheroff, N. (1993) J. Biol. Chem. 268, 14394-14398] indicated that the site of action for etoposide on topoisomerase II overlaps those of other DNA cleavage-enhancing drugs. Therefore, to further define interactions between drugs and the enzyme, the functional interaction domain (i.e., interaction domain defined by drug function) for quinolones on Drosophila topoisomerase II was mapped with respect to several classes of antineoplastic agents. This was accomplished by characterizing the effects of ciprofloxacin (a gyrase-targeted antibacterial quinolone) on the ability of etoposide, amsacrine, genistein, and the antineoplastic quinolone, CP-115,953, to enhance topoisomerase II-mediated DNA cleavage. Although ciprofloxacin interacts with the eukaryotic type II enzyme, it shows little ability to stimulate DNA cleavage. Ciprofloxacin attenuated cleavage enhancement by all of the above drugs. Similar results were obtained using a related quinolone, CP-80,080, as a competitor. In addition, kinetic analysis of DNA cleavage indicated that ciprofloxacin is a competitive inhibitor of CP-115,953 and etoposide. Finally, ciprofloxacin inhibited the cytotoxic actions of CP-115,953 and etoposide in mammalian cells to an extent that paralleled its in vitro attenuation of cleavage. These results strongly suggest that several structurally disparate DNA cleavage-enhancing antineoplastic drugs share an overlapping site of action on topoisomerase II. Based on the results of drug competition and mutagenesis studies, a model for the drug interaction domain on topoisomerase II is described.
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PMID:Quinolones share a common interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs. 906 21

The MICs of trovafloxacin, ciprofloxacin, ofloxacin, and sparfloxacin at which 90% of isolates are inhibited for 55 isolates of pneumococci were 0.125, 1, 4, and 0.5 microgram/ml, respectively. Resistant mutants of two susceptible isolates were selected in a stepwise fashion on agar containing ciprofloxacin at 2 to 10 times the MIC. While no mutants were obtained at the highest concentration tested, mutants were obtained at four times the MIC of ciprofloxacin (4 micrograms/ml) at a frequency of 1.0 x 10(-9). Ciprofloxacin MICs for these first-step mutants ranged from 4 to 8 micrograms/ml, whereas trovafloxacin MICs were 0.25 to 0.5 microgram/ml. Amplification of the quinolone resistance-determining region of the grlA (parC; topoisomerase IV) and gyrA (DNA gyrase) genes of the parents and mutants revealed that changes of the serine at position 80 (Ser80) to Phe or Tyr (Staphylococcus aureus coordinates) in GrlA were associated with resistance to ciprofloxacin. Second-step mutants of these isolates were selected by plating the isolates on medium containing ciprofloxacin at 32 micrograms/ml. Mutants for which ciprofloxacin MICs were 32 to 256 micrograms/ml and trovafloxacin MICs were 4 to 16 micrograms/ml were obtained at a frequency of 1.0 x 10(-9). Second-step mutants also had a change in GyrA corresponding to a substitution in Ser84 to Tyr or Phe or in Glu88 to Lys. Trovafloxacin protected from infection mice whose lungs were inoculated with lethal doses of either the parent strain or the first-step mutant. These results indicate that resistance to fluoroquinolones in S. pneumoniae occurs in vitro at a low frequency, involving sequential mutations in topoisomerase IV and DNA gyrase. Trovafloxacin MICs for wild-type and first-step mutants are within clinically achievable levels in the blood and lungs of humans.
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PMID:Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro. 912 24


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