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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The topoisomerase IV parC and parE genes from the wall-less organism Mycoplasma hominis PG21 were cloned and sequenced. The coupled genes are located far from the DNA gyrase genes gyrA and gyrB. They encode proteins of 639 and 866 amino acids, respectively. As expected, the encoded ParE and ParC proteins exhibit higher homologies with the topoisomerase IV subunits of the gram-positive bacteria Staphylococcus aureus and Streptococcus pneumoniae than with their Escherichia coli counterparts. The conserved regions include the Tyr residue of the active site and the region involved in quinolone resistance (quinolone resistance-determining region [QRDR]) in ParC and the ATP-binding site and the QRDR in ParE.
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PMID:Cloning and nucleotide sequences of the topoisomerase IV parC and parE genes of Mycoplasma hominis. 968 1

A hypothetical ORF of Mycoplasma gallisepticum with a putative 99-amino-acid product (ORF99) was noted previously in the upstream region from the type II topoisomerase gene. The amino acid sequence shows weak homology with the Escherichia coli histone-like protein HU. To identify and characterize the protein product of ORF99, we prepared mouse antiserum against recombinant GST-ORF99 fusion protein. The antiserum reacted with an 11-kDa peptide in the crude cell extract of M. gallisepticum, indicating that this protein is an ORF99 product. ORF99 protein binds to DNA, although its binding affinity is weaker than that of E. coli HU. When ORF99 was cloned in a plasmid and expressed in E. coli cells depleted of HU, Mu phage growth was strongly promoted in the cells, showing the presence of HU activity. The effect of IHF mutation was suppressed when a high level of ORF99 protein was expressed in an E. coli mutant deficient in IHF.
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PMID:Identification and characterization of HU protein from Mycoplasma gallisepticum. 970 29

Mycoplasma hominis mutants were selected stepwise for resistance to ofloxacin and sparfloxacin, and their gyrA, gyrB, parC, and parE quinolone resistance-determining regions were characterized. For ofloxacin, four rounds of selection yielded six first-, six second-, five third-, and two fourth-step mutants. The first-step mutants harbored a single Asp426-->Asn substitution in ParE. GyrA changes (Ser83-->Leu or Trp) were found only from the third round of selection. With sparfloxacin, three rounds of selection generated 4 first-, 7 second-, and 10 third-step mutants. In contrast to ofloxacin resistance, GyrA mutations (Ser83-->Leu or Ser84-->Trp) were detected in the first-step mutants prior to ParC changes (Glu84-->Lys), which appeared only after the second round of selection. Further analysis of eight multistep-selected mutants of M. hominis that were previously described (2) revealed that they carried mutations in ParE (Asp426-->Asn), GyrA (Ser83-->Leu) and ParE (Asp426-->Asn), GyrA (Ser83-->Leu) and ParC (Ser80-->Ile), or ParC (Ser80-->Ile) alone, depending on the fluoroquinolone used for selection, i.e., ciprofloxacin, norfloxacin, ofloxacin, or pefloxacin, respectively. These data indicate that in M. hominis DNA gyrase is the primary target of sparfloxacin whereas topoisomerase IV is the primary target of pefloxacin, ofloxacin, and ciprofloxacin.
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PMID:Alterations in topoisomerase IV and DNA gyrase in quinolone-resistant mutants of Mycoplasma hominis obtained in vitro. 973 54

Five clinical isolates of Mycoplasma hominis from three different patients were examined for resistance to fluoroquinolones; some of these isolates were probably identical. All five isolates harbored amino acid substitutions in the quinolone resistance-determining regions of both DNA gyrase (GyrA) and topoisomerase IV (ParC or ParE). Furthermore, the novobiocin MIC for three isolates showed a significant increase. This is the first characterization of fluoroquinolone-resistant clinical mycoplasma isolates from humans.
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PMID:Mutations in the gyrA, parC, and parE genes associated with fluoroquinolone resistance in clinical isolates of Mycoplasma hominis. 1010 8

Gemifloxacin is a fluoroquinolone antibacterial agent which has an enhanced affinity for topoisomerase i.v.. It has potent activity against most Gram-positive bacteria, particularly Streptococcus pneumoniae. Gemifloxacin is over 30-fold more active than ciprofloxacin and 4- to 8-fold more active than moxifloxacin against this pathogen. Gemifloxacin has excellent activity against Haemophilus influenzae and Moraxella catarrhalis, and is unaffected by beta-lactamase production. It is generally 2-fold less active than ciprofloxacin against most Enterobacteriaceae. Atypical respiratory pathogens (Legionella, Mycoplasma and Chlamydia spp.) are highly susceptible to gemifloxacin. Preliminary results from phase II trials show that oral gemifloxacin 320 mg/day produced bacteriological responses of 94.7% in patients with acute exacerbations of chronic bronchitis and 95% of patients with uncomplicated urinary tract infections. Adverse events included nausea, abdominal pain, headache and mild rash in patients and healthy volunteers treated with gemifloxacin 320 mg/day. Gemifloxacin has a low potential for mild phototoxicity (comparable to that of ciprofloxacin).
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PMID:Gemifloxacin. 1085 45

We report the cloning and characterization of the gyrA gene of the Mycoplasma hominis DNA gyrase, which was previously shown to be associated with quinolone resistance in this organism. The 2,733-bp gyrA gene encodes a protein of 911 amino acids with a calculated molecular mass of 102.5 kDa. As expected, M. hominis GyrA exhibits higher homology with the GyrA subunits of the gram-positive bacteria Clostridium acetobutylicum, Bacillus subtilis, Streptococcus pneumoniae, and Staphylococcus aureus than with its Escherichia coli counterpart. Knowing the entire sequence of the gyrA gene of M. hominis could be very useful for confirming the role of the GyrA subunit in fluoroquinolone resistance. Twenty-nine mutants of M. hominis were selected stepwise for resistance to trovafloxacin, a new potent fluoroquinolone, and their gyrA, gyrB, parC, and parE quinolone resistance-determining regions were characterized. Three rounds of selection yielded 3 first-step, 12 second-step, and 14 third-step mutants. The first-step mutants harbored a single substitution, Glu460-->Lys (E. coli coordinates), in ParE. GyrA changes, Ser83-->Leu, Glu87-->Lys, and Ala119-->Glu or Val, were found only in the second round of selection. At the third step, additional substitutions, at ParC Ser80, Ser81, and Glu84 and ParE Leu440, associated with high-level resistance to fluoroquinolones, appeared. Thus, high-level resistance to trovafloxacin required three steps and was associated with alterations in both fluoroquinolone targets. According to these genetic data, in M. hominis, as in Staphylococcus aureus and Streptococcus pneumoniae, topoisomerase IV seems to be the primary target of trovafloxacin.
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PMID:Cloning and nucleotide sequence of the DNA gyrase (gyrA) gene from Mycoplasma hominis and characterization of quinolone-resistant mutants selected in vitro with trovafloxacin. 1099 51

Mycoplasma gallisepticum enrofloxacin-resistant mutants were generated by stepwise selection in increasing concentrations of enrofloxacin. Alterations were found in the quinolone resistance-determining regions of the four target genes encoding DNA gyrase and topoisomerase IV from these mutants. This is the first description of such mutations in an animal mycoplasma species.
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PMID:Characterization of mutations in DNA gyrase and topoisomerase IV Involved in quinolone resistance of Mycoplasma gallisepticum mutants obtained in vitro. 1179 86

Resistant mutants of Mycoplasma gallisepticum were selected in vitro by passaging strains 10 times in increasing concentrations of enrofloxacin. The regions of gyrA/gyrB and parC/parE, encoding the quinolone resistance-determining regions (QRDRs) of DNA gyrase and DNA topoisomerase IV, respectively, of the mutants obtained during different passages were sequenced. Several mutations were found in the four fluoroquinolone targets. Substitution of Ser-83-->Arg in GyrA and Ser-80-->Leu or Trp in ParC QRDRs seem to have the greatest impact on resistance to fluoroquinolones. The results obtained also suggest that the preferential target of enrofloxacin in M. gallisepticum is DNA gyrase.
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PMID:Fluoroquinolone resistance in Mycoplasma gallisepticum: DNA gyrase as primary target of enrofloxacin and impact of mutations in topoisomerases on resistance level. 1235 6

Gatifloxacin, a novel 8-methoxyquinolone, was approved in April 2002 and launched in June 2002. Gatifloxacin shows a broad spectrum of antibacterial activity against Gram-negative, Gram-positive, anaerobic, and atypical pathogens. The activity is higher than those of other quinolones against RTI pathogens of S. pneumoniae including the penicillin-resistant strains, H. influenzae, Mycoplasma, and Chlamydia. This drug strongly inhibits the type II topoisomerase, DNA gyrase, and topoisomerase IV of S. pneumoniae and S. aureus to nearly the same extent, leading to the potent activity and low resistance. After an oral administration in humans, gatifloxacin is well absorbed and distributed, and the majority is excreted in the urine as the unchanged form. Its serum half-life is 7-8 h. The clinical effectiveness was observed for various infectious diseases including RTI and UTI. The bacterial eradication rate is 94.1% for Gram-positives, 90.7% for Gram-negatives, and 97.7% for anaerobes. In particular, gatifloxacin showed a high eradication rate of 98.7% for S. pneumoniae. The total cure rate and eradication rate of gatifloxacin in clinical studies are 91.1% and 93.3%, respectively, indicating that the potent activity and good PK profile account for its clinical efficacy.
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PMID:[Antibacterial property and clinical effect of gatifloxacin, a novel quinolone antibacterial agent]. 1283 39

Quinolone-resistant (QR) mutants of Mycoplasma bovirhinis strain PG43 (type strain) were generated by stepwise selection in increasing concentrations of enrofloxacin (ENR). An alteration was found in the quinolone resistance-determining region (QRDR) of the parC gene coding for the ParC subunit of topoisomerase IV from these mutants, but not in the gyrA, gyrB, and parE gene coding for the GyrA and GyrB subunits of DNA gyrase and the ParE subunit of topoisomerase IV. Similarly, such an alteration in QRDR of parC was found in the field isolates of M. bovirhinis, which possessed various levels of QR. The substitution of leucine (Leu) by serine (Ser) at position 80 of QRDR of ParC was observed in both QR-mutants and QR-isolates. This is the first report of QR based on a point mutation of the parC gene in M. bovirhinis.
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PMID:Characterization of a point mutation in the parC gene of Mycoplasma bovirhinis associated with fluoroquinolone resistance. 1522 51


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