Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Forty three strains of Neisseria gonorrhoeae with decreased sensitivity to quinolone antibiotics were detected amongst 2141 Australian isolates of gonococci examined in the years 1984 to 1990. The strains examined belonged to 23 different auxotype/serovar classes, were generally more resistant to other antibiotics and, in the majority of cases, were isolated from travellers entering or returning to Australia from SE Asia. Quinolone-sensitive wild-type gonococci became less sensitive to these agents in vitro at a relatively high frequency when grown in the presence of quinolone concentrations at or around the MIC (Mean Inhibitory Concentration) of the antibiotic. Further increments in the levels of quinolone resistance of the already less-sensitive gonococci were also produced by this means, but high-level resistance to these agents was not observed. This suggests that mechanisms other than alterations in the DNA-gyrase of the organisms were responsible for the changes seen. Although spread of quinolone resistance in gonococci in Australia is unlikely to be rapid, if these antibiotics are used in therapy, treatment regimens with higher rather than lower dosages of quinolone antibiotics should be employed.
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PMID:Characteristics of Neisseria gonorrhoeae isolated in Australia showing decreased sensitivity to quinolone antibiotics. 131 46

We selected the quinolone-resistant mutants from the protein F deficient Pseudomonas aeruginosa. The mutants showed cross-resistance to tetracycline, minocycline and chloramphenicol, but not to the beta-lactam antibiotics. The MIC of ofloxacin (OFLX) against the mutants, but not in the parent, became 2 to 4 times lower as the medium pH was raised from 6.5 to 8.5. The mutants accumulated about half as much OFLX as the parent. The OFLX accumulation in the mutants increased 6.5- to 8-fold in the presence of 100 mM carbonyl cyanide m-chlorophenylhydrazone, while that in the parent was 4-fold. The OFLX sensitivity of the mutant DNA-gyrase was comparable with that of the parent's enzyme. These results suggest that the resistance of these mutants to OFLX is associated with the membrane potential dependent drug efflux.
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PMID:Ofloxacin-resistant Pseudomonas aeruginosa mutants with elevated drug extrusion across the inner membrane. 165 10

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

The in vitro effect of human polymorphonuclear leukocytes on sub-MIC-ofloxacin-treated Pseudomonas aeruginosa was studied. Two bacteria strains were selected: one serum-sensitive and one serum-resistant. Exposure of the bacteria to subinhibitory concentrations of ofloxacin caused the bacteria to elongate into filaments. Pseudomonas aeruginosa was incubated with polymorphonuclear leukocytes and the bactericidal effect was quantitated by the reduction of CFUs. The killing of untreated and ofloxacin-treated bacteria did not differ when normal human serum was used for opsonization. However, when heat-inactivated serum or buffer was used, the killing of ofloxacin-treated bacteria was increased from 40% to 63% (P less than 0.05). Kinetic studies showed that this effect increased with prolonged incubation time. In addition, polymorphonuclear leukocytes incubated with ofloxacin had an increased bactericidal activity, probably due to intracellular uptake of the drug. Phagocytic ingestion of the bacteria was not influenced by ofloxacin-treatment. These findings support other investigations with DNA-gyrase inhibitors, which show that exposed bacteria become more susceptible to killing and that antibiotic-treated polymorphonuclear leukocytes react more strongly.
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PMID:Bactericidal effect of polymorphonuclear leukocytes on Pseudomonas aeruginosa pre-incubated in ofloxacin. 311 37

The recent piperazinyl-substituted mono-fluoroquinolones represent a family with some common characteristics on one side, and variable parameters on the other side. COMMON characteristics: same mechanism of action: DNA-gyrase inhibitors of the A subunit of topoisomerase; pH dependent antibacterial activity; a rather long post-antibiotic effect for both gram-positive and gram-negative bacteria; same physiochemical properties: organic acids, high pKa, lipophilicity. Some common pharmacokinetic parameters: low protein binding (less than 50%); high volume of distribution (greater than 1.5 l/kg) with good attainable tissue concentrations in lymph, blister fluid, renal tissue, prostate, bronchial secretions, saliva, aqueous humor, CSF, bone, bile; good intracellular penetration in macrophages, polynuclear neutrophils; high peak urinary concentrations markedly exceeding the MIC for virtually all bacterial urinary tract pathogens, even accounting for the increase in MIC in the urine, especially at lower (acidic) pH; low extraction ratio dialysis; similar adverse reactions; CNS, gastro-intestinal, photosensitivity, tendo-articular and cartilage toxicity. However, most other pharmacokinetic parameters are different from one fluoroquinolone to the other; oral bioavailability, peak serum levels (C max) as a measure of bioavailability, terminal half-life of elimination (t1/2) are all variable. The extent of metabolic biotransformation varies greatly, the two extremes being ofloxacin, showing a high metabolic stability, and pefloxacin, highly metabolized. The degree of antibacterial activity of different metabolites also varies greatly. The renal clearance of most fluoroquinolones, except pefloxacin, greatly exceeds normal glomerular filtration rate, suggesting additional renal tubular secretion. Renal elimination of most fluoroquinolones - except pefloxacin, is blocked by probenecid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative pharmacokinetic parameters of new systemic fluoroquinolones: a review. 329 63

The recent piperazinyl-substituted mono-fluoroquinolones represent a family with some common features on the one hand, and some variable parameters on the other. Some of the common features are: same mechanism of action (DNA-gyrase inhibitors of the A subunit of topoisomerase); pH-dependent antibacterial activity; a rather long post-antibiotic effect for both Gram-positive and Gram-negative bacteria; same physicochemical properties (organic acids, high pKa, lipophilicity). Common pharmacokinetic parameters include low protein binding (less than 50%); high volume of distribution (greater than 1 l/kg) with good tissue concentrations attainable in lymph, blister fluid, renal tissue prostate, bronchial secretions, saliva, aqueous humour, CSF, bone and bile; good intracellular penetration in macrophages and polynuclear neutrophils; high peak urinary concentrations, markedly exceeding the MIC for virtually all bacterial urinary tract pathogens, even accounting for the increase in MIC in the urine, especially at lower (acidic) pH; low extraction ratio dialysis; similar adverse reactions (CNS, gastrointestinal, photosensitivity, tendo-articular and cartilage toxicity). However, most other pharmacokinetic parameters are different from one fluoroquinolone to the other: oral bioavailability, peak serum levels (Cmax) as a measure of bioavailability, terminal half-life of elimination (t1/2) are all variable. The extent of metabolic biotransformation varies greatly, the two extremes being ofloxacin, showing a high metabolic stability and pefloxacin, highly metabolized. The degree of antibacterial activity of different metabolites also varies widely.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative pharmacokinetic parameters of new systemic fluoroquinolones. 329 83

In furtherance of our SAR study on the chemistry and antitumor activity of fused nitrogen heteroaromatic compounds, a series of linear, methyl-substituted derivatives of 5H- and 6H-indolo[2,3-b]quinolines were synthesized according to the modified Graebe-Ullmann reaction. To establish the relationship between the physicochemical and biological activities of indolo[2,3-b]quinolines, their lipophilic properties, cytotoxic and antimicrobial activity, and ability to induce topoisomerase II dependent pSP65 DNA cleavage in vitro were investigated. We found that the antimicrobial and cytotoxic activity of indolo[2,3-b]quinolines was strongly influenced by the position, and the number of methyl substituents and the presence of methyl group at pyridine nitrogen was essential for the cytotoxicity of these compounds. All indolo[2,3-b]quinolines belonging to the 5H series, i.e., bearing a methyl group on the pyridine nitrogen, showed significant activity against procaryotic and eucaryotic organisms. They inhibited the growth of Gram-positive bacteria and pathogenic fungi at MIC range 3 x 10(-2) to 2.5 x 10(-1) mumol/mL, displayed cytotoxicity against KB cells ID50 in the range 2 x 10(-3) to 9 x 10(-3) mumol/mL, and stimulated the formation of calf thymus topoisomerase II mediated DNA cleavage at concentration between 0.4 and 10 microM. None of the indolo[2,3-b]quinolines belonging to the 6H series, i.e., lacking a methyl group on the pyridine nitrogen, was active in analogous tests. Of the investigated compounds, the most active was 2,5,9,11-tetramethyl-5H-indolo[2,3-b]quinoline, a compound bearing the highest number of symmetrically distributed methyl groups. The interaction of indolo[2,3-b]quinolines with DNA was studied by measuring the increase of calf thymus DNA denaturating temperature (Tm). The delta Tm values for the 5H series were found to be about 10 times as high as those for the 6H compounds. Indolo[2,3-b]quinolines with the highest number of methyl groups had the greatest contribution to the increase in the Tm of calf thymus DNA. The values of delta Tm reached 19 degrees C and 1.6 degrees C for the most substituted compounds of both series.
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PMID:Synthesis and structure-activity relationship of methyl-substituted indolo[2,3-b]quinolines: novel cytotoxic, DNA topoisomerase II inhibitors. 793 79

Mutations in the flqA (formerly ofx/cfx) resistance locus of Staphylococcus aureus were previously shown to be common after first-step selections for resistance to ciprofloxacin and ofloxacin and to map on the S. aureus chromosome distinctly from gyrA, gyrB, and norA.grlA and grlB, the genes for the topoisomerase IV of S. aureus, were identified from a genomic lambda library on a common KpnI fragment, and grlB hybridized specifically with the chromosomal SmaI A fragment, which contains the flqA locus. Amplification of grlA sequences (codons 1 to 251) by PCRs from nine independent single-step flqA mutants, one multistep mutant, and the parent strain identified mutations encoding a change from Ser to Phe at position 80 in four mutants, a novel change from Ala to either Glu or Pro at position 116 in three mutants, and no change in three mutants. In the multistep mutant, another resistance locus, flqC, was mapped by transformation to the chromosomal SmaI G fragment by linkage to omega(ch::Tn551)1051 (58%) and nov (97.9%), which encodes resistance to novobiocin. This fragment contains the gyrA gene, and flqC mutants had a mutation in gyrA encoding a change from Ser to Leu at position 84, a change previously found in resistant clinical isolates. In genetic outcrosses, the flqC (gyrA) mutation expressed resistance only in flqA mutants, including those with both types of grla mutations. The silent mutant allele of gyrA was present in a flqA background and expressed resistance only upon introduction of a grlA mutation. At fourfold the MIC of ciprofloxacin, the bactericidal activity of ciprofloxacin was reduced in a grlA mutant and was abolished in gyrA grlA double mutants. These findings provide direct genetic evidence that topoisomerase IV is the primary target of current fluoroquinolones in S. aureus and that this effect may result from the greater sensitivity of topoisomerase IV relative to that of DNA gyrase to these agents. Furthermore, resistance from an altered DNA gyrase requires resistant topoisomerase IV for its expression.
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PMID:Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus. 884 98

Fifteen strains of Escherichia coli with MICs of ciprofloxacin (CIP) between 0.015 and 256 micrograms/ml were examined for the presence of mutations in the quinolone resistance-determining region of the gyrA gene and in an analogous region of the parC gene. No mutation was found in a susceptible isolate (MIC of CIP, 0.015 microgram/ml). Four moderately resistant strains (MIC of CIP 0.06 to 4 micrograms/ml) carried one gyrA mutation affecting serine 83, but in only one strain was an additional parC mutation (Gly-78 to Asp) detected. All ten highly resistant strains examined (MIC of CIP, > 4 micrograms/ml) carried two gyrA mutations affecting residues serine 83 and aspartate 87, and at least one parC mutation. These parC mutations included alterations of serine 80 to arginine or isoleucine and glutamate 84 to glycine or lysine. The parC+ and two mutant alleles (parCI-80 and parCI-80,G-84) were inserted into the mobilizable vector pBP507. Transfer of a plasmid-coded parC+ allele into parC+ strains did not alter the susceptibilities towards ciprofloxacin or nalidixic acid, while a significant increase in susceptibility was detectable for parC mutants. This increase, however, did not restore wild-type susceptibility, whereas transfer of a plasmid-coded gyrA+ allele alone or in combination with parC+ did. These data are in agreement with the view that topoisomerase IV is a secondary, less sensitive target for quinolone action in Escherichia coli and that the development of high-level fluoroquinolone resistance in E. coli requires at least one parC mutation in addition to the gyrA mutation(s).
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PMID:Genetic evidence for a role of parC mutations in development of high-level fluoroquinolone resistance in Escherichia coli. 884 44

The locus nfxD, which contributes to high-level quinolone resistance in Escherichia coli KF111b (gyrAr nfxB nfxD), is only expressed in the presence of a gyrA mutation, and maps to the region of the parC and parE genes, was outcrossed into strain KF130, creating strain DH161 (gyrAr nfxD). DNA sequence analysis of DH161 revealed no changes in the topoisomerase IV parC quinolone resistance-determining region but did identify a single T-to-A mutation in parE at codon 445, leading to a change from Leu to His. Full-length cloned parE+ partially complemented the resistance phenotype in KF111b and DH161, but did not complement the resistance phenotype in strain KF130 (gyrAr). No complementation was seen with cloned, truncated parE+. To confirm these findings, gyrAr was first outcrossed from KF130 into E. coli W3110parE10 [parE temperature sensitive(Ts)] and KL16. The transduced strains KL16 and W3110parE10 were subsequently transformed with plasmids containing cloned parE from DH161 or KL16. Cloned parE from DH161 increased norfloxacin resistance in the parE(Ts) background twofold at 30 degrees C and fourfold at 42 degrees C compared to those for cloned parE from KL16. The same experiment with a non-Ts background revealed a twofold increase in the norfloxacin MIC at both 30 and 42 degrees C. These data identify the nfxD conditional resistance locus as a mutant allele of parE. This report is the first of a quinolone-resistant parE mutant and confirms the role of topoisomerase IV as a secondary target of norfloxacin in E. coli.
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PMID:Quinolone resistance locus nfxD of Escherichia coli is a mutant allele of the parE gene encoding a subunit of topoisomerase IV. 898 Jul 75


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