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)

The L2 reference strain of Chlamydia trachomatis was exposed to subinhibitory concentrations of ofloxacin (0.5 microg/ml) and sparfloxacin (0.015 microg/ml) to select fluoroquinolone-resistant mutants. In this study, two resistant strains were isolated after four rounds of selection. The C. trachomatis mutants presented with high-level resistance to various fluoroquinolones, particularly to sparfloxacin, for which a 1,000-fold increase in the MICs for the mutant strains compared to the MIC for the susceptible strain was found. The MICs of unrelated antibiotics (doxycycline and erythromycin) for the mutant strains were identical to those for the reference strain. The gyrase (gyrA, gyrB) and topoisomerase IV (parC, parE) genes of the susceptible and resistant strains of C. trachomatis were partially sequenced. A point mutation was found in the gyrA quinolone-resistance-determining region (QRDR) of both resistant strains, leading to a Ser83-->Ile substitution (Escherichia coli numbering) in the corresponding protein. The gyrB, parC, and parE QRDRs of the resistant strains were identical to those of the reference strain. These results suggest that in C. trachomatis, DNA gyrase is the primary target of ofloxacin and sparfloxacin.
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PMID:Sequencing of gyrase and topoisomerase IV quinolone-resistance-determining regions of Chlamydia trachomatis and characterization of quinolone-resistant mutants obtained In vitro. 975 44

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

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

ABT-492 demonstrated potent antibacterial activity against most quinolone-susceptible pathogens. The rank order of potency was ABT-492 > trovafloxacin > levofloxacin > ciprofloxacin against quinolone-susceptible staphylococci, streptococci, and enterococci. ABT-492 had activity comparable to those of trovafloxacin, levofloxacin, and ciprofloxacin against seven species of quinolone-susceptible members of the family Enterobacteriaceae, although it was less active than the comparators against Citrobacter freundii and Serratia marcescens. The activity of ABT-492 was greater than those of the comparators against fastidious gram-negative species, including Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Legionella spp. and against Pseudomonas aeruginosa and Helicobacter pylori. ABT-492 was as active as trovafloxacin against Chlamydia trachomatis, indicating good intracellular penetration and antibacterial activity. In particular, ABT-492 was more active than trovafloxacin and levofloxacin against multidrug-resistant Streptococcus pneumoniae, including strains resistant to penicillin and macrolides, and H. influenzae, including beta-lactam-resistant strains. It retained greater in vitro activity than the comparators against S. pneumoniae and H. influenzae strains resistant to other quinolones due to amino acid alterations in the quinolone resistance-determining regions of the target topoisomerases. ABT-492 was a potent inhibitor of bacterial topoisomerases, and unlike the comparators, DNA gyrase and topoisomerase IV from either Staphylococcus aureus or Escherichia coli were almost equally sensitive to ABT-492. The profile of ABT-492 suggested that it may be a useful agent for the treatment of community-acquired respiratory tract infections, as well as infections of the urinary tract, bloodstream, and skin and skin structure and nosocomial lung infections.
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PMID:In vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone. 1450 39

Gemifloxacin is a dual targeted fluoroquinolone with potent in vitro activity against Gram-positive, -negative and atypical human pathogens--pathogens considered to be important causes of community-acquired respiratory tract infections. Gemifloxacin demonstrates impressive minimal inhibitory concentrations (MIC 90 ) values against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae and Legionella spp., with MIC 90 values reported to be 0.016-0.06, < 0.0008-0.06, 0.008-0.3, 0.25, 0.125 and 0.016-0.07 microg/ml, respectively. Gemifloxacin is also active in vitro against a broad range of Gram-negative bacilli with MIC 90 values against the Enterobacteriaceae in the range of 0.016 to > 16 microg/ml ( Escherichia coli and Providencia stuartii, respectively), with the majority of the genus having MIC 90 drug concentrations < 0.5 microg/ml. The in vitro activity of gemifloxacin against anaerobic organisms is variable. The MIC values for gemifloxacin are not affected by beta-lactamase production nor by penicillin or macrolide resistance in S. pneumoniae. Gemifloxacin is approved by the FDA to be clinically efficacious against multi-drug resistant S. pneumoniae. The pharmacokinetics of gemifloxacin are such that the drug can be administered orally once-daily to yield or achieve sustainable drug concentrations exceeding the MIC values of clinically important organisms. Gemifloxacin has been shown to target both DNA gyrase (preferred target) and topoisomerase IV (secondary target) - enzymes critical for DNA replication and organism survival - against clinical isolates of S. pneumoniae. This dual targeting activity is thought to be important for reducing the likelihood for selecting for quinolone resistance. Gemifloxacin has been investigated and approved for therapy in patients with community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis. In one study, more patients receiving gemifloxacin compared to clarithromycin remained free of exacerbations for longer periods of time (p < 0.016) and gemifloxacin had a shorter time to eradication of H. influenzae than did clarithromycin (p < 0.02). From efficacy studies, gemifloxacin was found to have an adverse profile that was comparable with other compounds. The most frequent side effects were diarrhoea, abdominal pain and headache. Gemifloxacin is a welcomed addition to currently available agents for the treatment of community-acquired lower respiratory tract infections. Other potential indications appear to be within the spectrum of this compound.
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PMID:Gemifloxacin: a new fluoroquinolone. 1515 13

A series of ureido derivatives incorporating a highly derivatized quinolone scaffold were prepared by a succession of original steps. The lead molecules of these compounds are the quinolone antibacterials of the nalidixic acid/ciprofloxacin type and they target, similar to these clinically used agents, the DNA gyrase/topoisomerase IV of pathogenic bacteria. These new quinolones are claimed to act as efficient antibacterials against a large number of drug-resistant bacteria such as Staphylococcus spp., Enterococcus spp., Streptococcus spp., Acinetobacter baumannii, Bacteroides bivius, Burkholderia spp., Chlamydia spp., Chlamydophila pneumoniae.
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PMID:Heterocyclic urea derivatives and methods of use thereof (WO2010142978). 2226 34

Chlamydia is a medically important bacterium that infects eukaryotic cells. Temporal expression of chlamydial genes during the intracellular infection is proposed to be regulated by changes in DNA supercoiling levels. To understand how chlamydial supercoiling levels are regulated, we purified and analyzed three putative Chlamydia trachomatis topoisomerases. As predicted by sequence homology, CT189/190 are the two subunits of DNA gyrase, whereas CT643 is a topoisomerase I. CT660/661 have been predicted to form a second DNA gyrase, but the reconstitute holoenzyme decatenated and relaxed DNA, indicating that the proteins are subunits of topoisomerase IV. Promoter analysis showed that each topoisomerase is transcribed from its own operon by the major chlamydial RNA polymerase. Surprisingly, all three topoisomerase promoters had higher activity from a more supercoiled DNA template. This supercoiling-responsivesness is consistent with negative feedback control of topoisomerase I and topoisomerase IV expression, which is typical of other bacteria. However, activation of the chlamydial gyrase promoter by increased supercoiling is unorthodox compared with the relaxation-induced transcription of gyrase in other bacteria. We present a model in which supercoiling levels during the intracellular chlamydial developmental cycle are regulated by unusual positive feedback control of the gyrase promoter and the temporal expression of three topoisomerases.
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PMID:Functional analysis of three topoisomerases that regulate DNA supercoiling levels in Chlamydia. 2644 25

Mycoplasma genitalium has been associated with infections of the genitourinary tract, and prevalence is secondary to Chlamydia trachomatis The clinical observation of increasing treatment failure indicating antibiotic resistance, especially in cases of recurrent urethritis, has been confirmed by molecular testing. Mutations in the 23S rRNA gene can cause macrolide resistance, and topoisomerase/gyrase mutations can cause fluoroquinolone resistance. In this study, 115 M. genitalium DNA-positive samples were analyzed. Eighty-nine (77.4%) samples had a 23S rRNA mutation present, and 26 (22.6%) were wild type (no resistance mutation). Fluoroquinolone mutation screening was performed on 86 (74.8%) of the 115 samples, of which 20 (23.3%) samples had a mutation or mutations associated with increased resistance. This study shows the increasing antibiotic resistance in New Zealand and the need for appropriate guidelines to treat at-risk patients.
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PMID:Mycoplasma genitalium Macrolide and Fluoroquinolone Resistance Detection and Clinical Implications in a Selected Cohort in New Zealand. 2887 4