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 antibacterial activities and target inhibition of 15 quinolones against grlA and gyrA mutant strains were studied. The strains were obtained from wild-type Staphylococcus aureus MS5935 by selection with norfloxacin and nadifloxacin, respectively. The antibacterial activities of most quinolones against both mutant strains were lower than those against the wild-type strain. The ratios of MICs for the gyrA mutant strain to those for the grlA mutant strain (MIC ratio) varied from 0.125 to 4. The ratios of 50% inhibitory concentrations (IC(50)s) of quinolones against topoisomerase IV to those against DNA gyrase (IC(50) ratios) also varied, from 0.177 to 5.52. A significant correlation between the MIC ratios and the IC(50) ratios was observed (r = 0.919; P < 0.001). These results suggest that the antibacterial activities of quinolones against the wild-type strain are involved not only in topoisomerase IV inhibition but also in DNA gyrase inhibition and that the target preference in the wild-type strain can be anticipated by the MIC ratios. Based on the MIC ratios, the quinolones were classified into three categories. Type I quinolones (norfloxacin, enoxacin, fleroxacin, ciprofloxacin, lomefloxacin, trovafloxacin, grepafloxacin, ofloxacin, and levofloxacin) had MIC ratios of <1, type II quinolones (sparfloxacin and nadifloxacin) had MIC ratios of >1, and type III quinolones (gatifloxacin, pazufloxacin, moxifloxacin, and clinafloxacin) had MIC ratios of 1. Type I and type II quinolones seem to prefer topoisomerase IV and DNA gyrase, respectively. Type III quinolones seem to target both enzymes at nearly the same level in bacterial cells (a phenomenon known as the dual-targeting property), and their IC(50) ratios were approximately 2.
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PMID:Target preference of 15 quinolones against Staphylococcus aureus, based on antibacterial activities and target inhibition. 1170 37

Levofloxacin resistance in Streptococcus pneumoniae is rare, requiring at least two mutations in the quinolone resistance-determining region (QRDR) of topoisomerase IV and DNA gyrase. The prevalence of single QRDR mutations in these genes is unknown. Of 9,438 levofloxacin-susceptible pneumococci from the TRUST 4 surveillance study (1999-2000), 528 strains (MICs of 0.5 to 2.0 microg/ml) were selected for analysis. For comparison, 214 levofloxacin-susceptible strains (MICs of 0.5 to 1 microg/ml) isolated between 1992 and 1996 were analyzed. Oligonucleotide probe assay and DNA sequencing were used to detect QRDR mutations leading to changes at Ser79 and Asp83 in ParC, Ser81 in GyrA, and Asp435 in ParE, the most frequently found substitutions among levofloxacin-resistant strains. Among the 1992 to 1996 isolates only one strain (levofloxacin MIC, 1 microg/ml) had a mutation (Ser79 to Phe in ParC). No single mutations were found among 270 TRUST 4 strains with levofloxacin MICs of 0.5 microg/ml. Among 244 strains for which levofloxacin MICs were 1 microg/ml, 15 strains (6.1%) had a parC mutation and 3 strains (1.2%) had a parE mutation. Of 14 strains for which levofloxacin MICs were 2 microg/ml, 10 strains (71%) had a parC mutation; no parE mutations were found. No gyrA mutations were detected. It was estimated that 4.5% of the 9,438 levofloxacin-susceptible TRUST 4 isolates (MICs, < or =0.06 to 2 microg/ml) had a single parC or parE QRDR mutation. Although there has been an increase in the prevalence of single-step mutants, the increase may have been overestimated due in part to differences in geographical distribution for the two sets of isolates.
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PMID:Prevalence of single mutations in topoisomerase type II genes among levofloxacin-susceptible clinical strains of Streptococcus pneumoniae isolated in the United States in 1992 to 1996 and 1999 to 2000. 1175 Nov 21

The resistance mechanisms to fluoroquinolones in Staphylococcus aureus were clarified by analyzing mutations in the genes encoding target enzymes, and examining the expression of the efflux pump, and determining the inhibitory activities of fluoroquinolones against the altered enzymes. Mutations in the grlA and gyrA genes of 344 clinical strains of S. aureus isolated in 1994 in Japan were identified by combinations of methods - single-strand conformation polymorphism analysis, restriction fragment length analysis, and direct sequencing - to identify possible relationships with fluoroquinolone resistance. Five types of single-point mutations and four types of double mutations were observed in the grlA gene in 204 strains (59.3%). Four types of single-point mutations and four types of double mutations were found in the gyrA gene in 188 strains (54.7%). Among these mutations, the grlA mutation of TCC --> TTC or TAC (Ser-80 --> Phe or Tyr) and the gyrA mutation of TCA --> TTA (Ser-84 --> Leu) were the principal ones, being detected in 137 (39.8%) and 121 (35.2%) isolates, respectively. A total of 15 types of mutation combinations within both genes were related to ciprofloxacin resistance (MIC greater than or equal 3.13 microg/ml) and were present in 193 mutants (56.1%). Strains containing mutations in both genes were highly resistant to ciprofloxacin (MIC50 =50 microg/ml). Those strains with the Ser-80 --> Phe or Tyr alteration in grlA, but wild type in gyrA showed a lower level of ciprofloxacin resistance (MIC50 less than or equal 12.5 microg/ml). Levofloxacin was active against 68 of 193 isolates (35.2%) with mutations at codon 80 of grlA in the presence or absence of concomitant mutations at codons 73, 84, or 88 in gyrA (MIC less than or equal 6.25 microg/ml). Sitafloxacin (DU-6859a) showed good activity in 186 of 193 isolates (96.4%), with an MIC of less than or equal 6.25 microg/ml. The contribution of membrane-associated multidrug efflux protein (NorA) expression to fluoroquinolone resistance was clarified by the checker-board titration method for determining the MIC of norfloxacin alone and in combination with carbonyl cyanide m-chlorophenylhydrazone. Among 344 clinical isolates, 139 strains (40.4%), in which the MIC of norfloxacin varied from 1.56 to >800 microg/ml, overexpressed the NorA protein. GrlA and GrlB proteins of topoisomerase IV, and GyrA and GyrB proteins of DNA gyrase encoded by genes with or without mutations were purified separately. The inhibitory activities of fluoroquinolones against the topoisomerase IV which contained a single amino acid change (Ser --> Phe at codon 80, Glu --> Lys at codon 84 of grlA, and Asp --> Asn at codon 432 of grlB) were from 5 to 95 times weaker than the inhibitory activities against the non-altered enzyme. These results suggest that the mutations in the corresponding genes may confer quinolone resistance; the active efflux pump, NorA, was considered to be the third quinolone-resistance mechanism. The numerous and complicated mutations seen may explain the rapid and widespread development of quinolone resistance described in S. aureus. Sitafloxacin showed good antibacterial activity against ciprofloxacin- or levofloxacin-resistant mutants because of its high inhibitory activity against both topoisomerase IV and DNA gyrase.
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PMID:Mechanism of quinolone resistance in Staphylococcus aureus. 1181 May 52

NCCLS agar dilution was used to test activity of telithromycin compared to clarithromycin, penicillin G, ciprofloxacin, levofloxacin, sparfloxacin and moxifloxacin against 26 pneumococci with defined quinolone resistance (type II topoisomerase and efflux) mechanisms. Thirteen strains were penicillin susceptible, six intermediate and seven resistant. Clarithromycin resistance (mef and/or erm) was seen in eight strains. Ciprofloxacin MICs (mg/L) were 8-64 compared to 1-32 (levofloxacin), 0.5 . or = 32 (sparfloxacin) and 0.125-4 (moxifloxacin). Telithromycin MIC50 and MIC90 values (mg/L) were 0.016 and 0.25, with only one strain having an MIC of 2 mg/L.
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PMID:Activity of telithromycin against 26 quinolone-resistant pneumococci with known quinolone-resistance mechanisms. 1184 16

The quinolone resistance-determining regions (QRDRs) of topoisomerase II and IV genes from Stenotrophomonas maltophilia ATCC 13637 were sequenced and compared with the corresponding regions of 32 unrelated S. maltophilia clinical strains for which ciprofloxacin MICs ranged from 0.1 to 64 microg/ml. GyrA (Leu-55 to Gln-155, Escherichia coli numbering), GyrB (Met-391 to Phe-513), ParC (Ile-34 to Arg-124), and ParE (Leu-396 to Leu-567) fragments from strain ATCC 13637 showed high degrees of identity to the corresponding regions from the phytopathogen Xylella fastidiosa, with the degrees of identity ranging from 85.0 to 93.5%. Lower degrees of identity to the corresponding regions from Pseudomonas aeruginosa (70.9 to 88.6%) and E. coli (73.0 to 88.6%) were observed. Amino acid changes were present in GyrA fragments from 9 of the 32 strains at positions 70, 85, 90, 103, 112, 113, 119, and 124; but there was no consistent relation to higher ciprofloxacin MICs. The absence of changes at positions 83 and 87, commonly involved in quinolone resistance in gram-negative bacteria, was unexpected. The GyrB sequences were identical in all strains, and only one strain (ciprofloxacin MIC, 16 microg/ml) showed a ParC amino acid change (Ser-80-->Arg). In contrast, a high frequency (16 of 32 strains) of amino acid replacements was present in ParE. The frequencies of alterations at positions 437, 465, 477, and 485 were higher (P < 0.05) in strains from cystic fibrosis patients, but these changes were not linked with high ciprofloxacin MICs. An efflux phenotype, screened by the detection of decreases of at least twofold doubling dilutions of the ciprofloxacin MIC in the presence of carbonyl cyanide m-chlorophenylhydrazone (0.5 microg/ml) or reserpine (10 microg/ml), was suspected in seven strains. These results suggest that topoisomerases II and IV may not be the primary targets involved in quinolone resistance in S. maltophilia.
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PMID:Topoisomerase II and IV quinolone resistance-determining regions in Stenotrophomonas maltophilia clinical isolates with different levels of quinolone susceptibility. 1185 Feb 46

The increase in the use of the fluoroquinolones, including for the treatment of lower respiratory tract infections, seems to be associated with a parallel increase in bacterial resistance. We studied the activity of penicillin and six fluoroquinolones against 101 viridans group streptococci isolated from blood (58 erythromycin-susceptible and 43 erythromycin-resistant). The percentage of strains not susceptible to penicillin was 35% and there were statistically significant differences in the percentages of penicillin resistance between erythromycin-susceptible and -resistant strains. The fluoroquinolones studied showed good activity against our viridans group streptococci independent of their susceptibility to erythromycin. The norfloxacin MIC(50) and MIC(90) were 8 and 16 mg/l, respectively. Ofloxacin and ciprofloxacin showed the same activity (MIC(50) 1 mg/l and MIC(90) 2 mg/l); levofloxacin was similar with MIC(50) and MIC(90) of 1 mg/l. The fluoroquinolones with enhanced activity were moxifloxacin and trovafloxacin (MIC(50) 0.12 mg/l and MIC(90) 0.25 mg/l). However, we found two strains resistant to trovafloxacin (MIC = 4 mg/l) that showed reduced susceptibility to all the fluoroquinolones tested, including moxifloxacin (MIC = 2 mg/l). Mutations in the topoisomerase genes parC and gyrA have been shown to occur in strains with reduced susceptibility; therefore, ongoing surveillance for the development of fluoroquinolone resistance in viridans streptococci is necessary.
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PMID:[In vitro activity of six fluoroquinolones and penicillin against 101 viridans group streptococci characterized by their susceptibility to erythromycin]. 1185 83

OBJECTIVE: To determine whether similar mutations to quinolone resistance in the gyrA subunit of DNA gyrase and the parC subunit of topoisomerase IV are occurring independently in genotypically unrelated clinical isolates of Acinetobacter spp., or whether worldwide clonal spread of particular resistant strains is occurring. METHODS: The genotypic relationships of 25 nosocomial isolates of Acinetobacter spp. from 15 locations in 11 different countries worldwide were examined by randomly amplified polymorphic DNA analysis. Quinolone resistance-determining regions of gyrA and parC were amplified by PCR and mutations were analyzed by restriction digestion with Hinfl and DNA sequencing. RESULTS: Twenty-four of the 25 Acinetobacter isolates were genotypically heterogeneous and 12 were resistant to both nalidixic acid and ciprofloxacin. Analysis of conserved gyrA and parC regions showed that all isolates with a ciprofloxacin MIC of 4 mg/L had a substitution of Ser83 with either Leu or Phe in the GyrA protein. Five of six isolates with ciprofloxacin MICs of 64 mg/L had additional substitutions of Ser80 with Leu in the ParC protein. CONCLUSIONS: Similar mutations to quinolone resistance, predominantly at codons 82--83 of gyrA, are occurring independently in genotypically distinct isolates of Acinetobacter spp. from different worldwide locations. Most isolates with high ciprofloxacin MICs also exhibited secondary mutations in parC at codons 79--80.
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PMID:Molecular epidemiology of quinolone resistance in Acinetobacter spp. 1186 39

The in vitro and in vivo activity of T-3912, a novel non-fluorinated topical quinolone, was compared with that of nadifloxacin, ofloxacin, levofloxacin, clindamycin, erythromycin and gentamicin. The in vitro activity of T-3912 against methicillin-susceptible Staphylococcus aureus, ofloxacin-resistant and methicillin-resistant S. aureus, Staphylococcus epidermidis, ofloxacin-resistant S. epidermidis, penicillin-resistant Streptococcus pneumoniae and Propionibacterium acnes was four-fold to 16 000-fold greater than that of other agents at the MIC90 for the clinical isolates. The activity of T-3912 was not influenced by grlA mutation in S. aureus, and the degree of MIC increase of T-3912 for grlA-gyrA double and triple mutants was lowest among the quinolones tested (nadifloxacin, levofloxacin and ofloxacin). The inhibitory activity of T-3912 was compared with other quinolones for DNA gyrase and topoisomerase IV of S. aureus SA113. T-3912 showed the greatest inhibitory activity for both enzymes among the quinolones tested. The isolation frequency of spontaneous mutants resistant to T-3912 was < 1.7 x 10(-9) and < 2.0 x 10(-9) for S. aureus SA113 and P. acnes JCM 6425, respectively. Furthermore, resistance to T-3912 could not be clearly detected in the 28th transfer by the serial passage method. T-3912 exhibited more potent bactericidal activity against S. aureus and P. acnes than nadifloxacin and clindamycin in a short time period. T-3912 in a 1% gel formulation showed good therapeutic activity against a burn infection model caused by S. aureus SA113, P. acnes JCM6425 and multidrug-resistant S. aureus F-2161. These results indicate that T-3912 is potentially a useful quinolone for the treatment of skin and soft-tissue infections and that its potent bactericidal activity might be able to shorten the treatment period.
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PMID:In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. 1186 45

Four amino acid substitutions, two in GyrA and two in ParC subunits of DNA gyrase and topoisomerase IV, respectively, are commonly responsible for fluoroquinolone resistance in Escherichia coli. In this study, an economical and time-efficient mismatch amplification mutation assay (MAMA) PCR was developed to detect mutations in the chromosomal gyrA and parC genes causing these substitutions. One hundred and twenty-one clinical E. coli isolates were tested by this assay, and the results confirmed that accumulation of amino acid alterations in GyrA and ParC correlates closely with stepwise increases in the MIC of ciprofloxacin.
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PMID:Use of a rapid mismatch PCR method to detect gyrA and parC mutations in ciprofloxacin-resistant clinical isolates of Escherichia coli. 1186 58

The frequency of fluoroquinolone-resistant Streptococcus pneumoniae has increased as fluoroquinolone administration for treatment of respiratory tract infections has increased. Levofloxacin treatment failed in a patient who had pneumococcal pneumonia and had received three previous courses of levofloxacin therapy. Susceptibility testing revealed high-level resistance to levofloxacin (minimum inhibitory concentration [MIC] > 32 microg/ml), and cross-resistance to moxifloxacin (MIC 4 microg/ml), trovafloxacin (6 microg/ml), and gatifloxacin (12 microg/ml). Sequencing of the quinolone-resistance determining region revealed a mutation of serine-81 to phenylalanine (Ser81-->Phe) in the gyrA region of DNA gyrase and a Ser79-->Phe mutation in the parC region of topoisomerase IV The patient was treated successfully with intravenous ceftriaxone followed by oral cefprozil. Clinicians must be aware of local resistance patterns and the potential for fluoroquinolone treatment failures in patients with infections caused by S. pneumoniae.
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PMID:Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. 1189 97


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