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)

DX-619, a novel des-fluoro(6) quinolone, was 16- to 32-fold, twofold, and four- to eightfold more potent than ciprofloxacin, gemifloxacin, and garenoxacin, respectively, against wild-type Staphylococcus aureus. DX-619 manifested equal fourfold increases in MIC against a common parC mutant and a common gyrA mutant and selected for mutants at up to two- to fourfold its MIC, consistent with dual-targeting properties. Of the four independent single-step mutants selected, two had new single mutations in parC (V87F and R17H), and two shared a new gyrA mutation (A26V), one with an additional deletion mutation in parE (delta215-7). By allelic exchange, the ParC but not the GyrA or ParE mutation was shown to be fully responsible for the resistance phenotypes, suggesting an as yet undefined mechanism of resistance operating in conjunction with type II topoisomerase mutations contributed to resistance to DX-619. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that DX-619 had similar activity against topoisomerase IV and gyrase (50% stimulation of cleavage complexes concentration, 1.25 and 0.62 to 1.25 mug/ml, respectively). Susceptibility studies with DX-619 and an array of efflux pump substrates with and without reserpine, an inhibitor of efflux pumps, suggested that resistance in DX-619-selected mutants is affected by mechanisms other than mutations in topoisomerases or known reserpine-inhibitable pumps in S. aureus and thus are likely novel.
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PMID:DX-619, a novel des-fluoro(6) quinolone manifesting low frequency of selection of resistant Staphylococcus aureus mutants: quinolone resistance beyond modification of type II topoisomerases. 1630 72

To substantiate a common genetic background of ciprofloxacin-resistant Enterococcus faecium, 32 ciprofloxacin-resistant (Cip(r)) and 31 ciprofloxacin-susceptible (Cip(s)) isolates from outbreaks, clinical infections, surveillances, and animals from 10 different countries were genotyped by multilocus sequence typing. Additionally, susceptibilities to ampicillin and vancomycin and the presence of esp were determined and the quinolone resistance-determining regions of parC, gyrA, parB, and gyrE were sequenced. High-level Cip(r) (MIC > or = 64 microg/ml) due to point mutations in the quinolone resistance-determining region was unique to a distinct hospital-adapted genetic complex in E. faecium, previously designated CC17. Low-level Cip(r) (MIC = 4 microg/ml) in non-CC17 strains is not attributable to point mutations in any subunit of the topoisomerase genes, and the mechanism of resistance remains unclear. Acquisition of mutations in parC and gyrA, leading to high-level Cip(r), is, in addition to ampicillin resistance and the presence of a putative pathogenicity island, another cumulative step in hospital adaptation of CC17.
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PMID:High-level ciprofloxacin resistance from point mutations in gyrA and parC confined to global hospital-adapted clonal lineage CC17 of Enterococcus faecium. 1651 94

The ability of Mycoplasma hyopneumoniae to persist despite fluoroquinolone treatments was investigated with pigs. Groups of specific-pathogen-free pigs were experimentally infected with M. hyopneumoniae strain 116 and treated with marbofloxacin at the therapeutic dose (TD) or half of the therapeutic dose (TD/2) for 3 days. Results showed that, despite tissue penetration of marbofloxacin, particularly in the trachea and the tracheal secretions, the treatments did not have any influence on M. hyopneumoniae recovery from tracheal swabs. Mycoplasmas were also isolated from inner organs and tissues such as liver, spleen, kidneys, and bronchial lymph nodes. Recontamination of pigs via environment could not explain mycoplasma persistence after medication, as decontamination of pigs and allocation to a new disinfected environment did not have any significant effect on the phenomenon. A significant decrease in the susceptibility level to marbofloxacin of 12 mycoplasma clones reisolated after the treatments (TD/2 and TD) was observed. Two point mutations were found in the ParC quinolone resistance-determining region (QRDR) of DNA topoisomerase IV (Ser80-->Phe and Asp84-->Asn), and one point mutation was observed just behind the QRDR of ParC (Ala116-->Glu). This is the first time that mutations in a gene coding for topoisomerase IV have been described for M. hyopneumoniae after in vivo marbofloxacin treatments in experimentally infected pigs. However, development of resistance is not sufficient to explain M. hyopneumoniae persistence in vivo since (i) marbofloxacin concentrations were above the marbofloxacin MIC of the wild-type strain and (ii) mycoplasmas reisolated after a single injection of marbofloxacin did not display an increased marbofloxacin MIC.
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PMID:Persistence of Mycoplasma hyopneumoniae in experimentally infected pigs after marbofloxacin treatment and detection of mutations in the parC gene. 1672 52

WCK 771 is a broad-spectrum fluoroquinolone with enhanced activity against quinolone-resistant staphylococci. To understand the impact of the target-level interactions of WCK 771 on its antistaphylococcal pharmacodynamic properties, we determined the MICs for genetically defined mutants and studied the mutant prevention concentrations (MPCs), the frequency of mutation, and the cidality against the wild type and double mutants. There was a twofold increase in the MICs of WCK 771 for single gyrA mutants, indicating that DNA gyrase is its primary target. All first- and second-step mutants selected by WCK 771 revealed gyrA and grlA mutations, respectively. The MICs of WCK 771 and clinafloxacin were found to be superior to those of other quinolones against strains with double and triple mutations. WCK 771 was also cidal for high-density double mutants at low concentrations. WCK 771 and clinafloxacin showed narrow mutant selection windows compared to those of the other quinolones. Against a panel of 50 high-level quinolone-resistant clinical isolates of staphylococci (ciprofloxacin MIC > or = 16 microg/ml), the WCK 771 MPCs were < or =2 microg/ml for 68% of the strains and < or =4 microg/ml for 28% of the strains. Our results demonstrate that gyrA is the primary target of WCK 771 and that it has pharmacodynamic properties remarkably different from those of quinolones with dual targets (garenoxacin and moxifloxacin) and topoisomerase IV-specific quinolones (trovafloxacin). WCK 771 displayed an activity profile comparable to that of clinafloxacin, a dual-acting quinolone with a high affinity to DNA gyrase. Overall, the findings signify the key role of DNA gyrase in determining the optimal antistaphylococcal features of quinolones.
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PMID:The anti-methicillin-resistant Staphylococcus aureus quinolone WCK 771 has potent activity against sequentially selected mutants, has a narrow mutant selection window against quinolone-resistant Staphylococcus aureus, and preferentially targets DNA gyrase. 1694 59

To understand better the mechanisms of fluoroquinolone resistance in Enterococcus faecalis, fluoroquinolone-resistant mutants isolated from Ent. faecalis ATCC 29212 by stepwise selection with sparfloxacin (SPX) and norfloxacin (NOR) were analysed. The results showed the following. (i) In general, fluoroquinolone-resistance mechanisms in Ent. faecalis are similar to those in other Gram-positive bacteria, such as Staphylococcus aureus and Streptococcus pneumoniae, namely, mutants with amino acid changes in both GyrA and ParC exhibited high fluoroquinolone resistance, and single GyrA mutants and a single ParC mutant were more resistant to SPX and NOR, respectively, than the parent strain, indicating that the primary targets of SPX and NOR in Ent. faecalis are DNA gyrase and topoisomerase IV, respectively. (ii) Alterations in GyrB (DeltaKGA, residues 395-397) and ParE (Glu-459 to Lys) were associated with fluoroquinolone resistance in some mutants. Moreover, the facts that the NOR MIC, but not the SPX MIC, decreased in the presence of multidrug efflux pump inhibitors, that NOR accumulation decreased in the cells, and that the EmeA mRNA expression level did not change, strongly suggested that a NorA-like efflux pump, rather than EmeA, was involved in resistance to NOR.
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PMID:Topoisomerase mutations and efflux are associated with fluoroquinolone resistance in Enterococcus faecalis. 1700 89

Serial passage of a clinical isolate of Streptococcus pneumoniae, in the presence of moxifloxacin, gatifloxacin or gemifloxacin, gave rise to resistant isolates. Non-susceptibility as defined by Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) breakpoints arose on Days 10, 11, and 12 with gatifloxacin, gemifloxacin, and moxifloxacin respectively. Moxifloxacin and gatifloxacin selected for a single step quinolone-resistant-determining-region (QRDR) mutation in DNA gyrase (GyrA) on Day 4 and 7 respectively, whereas gemifloxacin selected simultaneously for multi-step mutations in gyrase and topoisomerase IV (ParC) on Day 17 and activated a non-reserpine inhibited efflux mechanism by Day 4. As found in clinical isolates, mutations included Ser-81-Phe and Glu-85-Lys in GyrA and Ser-79-Phe or Asp-83-Tyr in ParC. At high MICs, moxifloxacin showed a previously unreported 4 amino-acid deletion in GyrB as well as a more unusual substitution Ser-79-Leu/Ile in ParC. Gemifloxacin showed a 2- to 16-fold greater activity than moxifloxacin or gatifloxacin against strains with two or more QRDR mutations, however, its potency did not translate to nonsusceptibility and gemifloxacin MIC values were either at or well above the CLSI nonsusceptible breakpoint concentration.
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PMID:Relative potential for selection of quinolone-resistance-determining-region mutations in Streptococcus pneumoniae by gemifloxacin, gatifloxacin and moxifloxacin. 1702 92

A structure-guided drug design approach was used to optimize a novel series of aminobenzimidazoles that inhibit the essential ATPase activities of bacterial DNA gyrase and topoisomerase IV and that show potent activities against a variety of bacterial pathogens. Two such compounds, VRT-125853 and VRT-752586, were characterized for their target specificities and preferences in bacteria. In metabolite incorporation assays, VRT-125853 inhibited both DNA and RNA synthesis but had little effect on protein synthesis. Both compounds inhibited the maintenance of negative supercoils in plasmid DNA in Escherichia coli at the MIC. Sequencing of DNA corresponding to the GyrB and ParE ATP-binding regions in VRT-125853- and VRT-752586-resistant mutants revealed that their primary target in Staphylococcus aureus and Haemophilus influenzae was GyrB, whereas in Streptococcus pneumoniae it was ParE. In Enterococcus faecalis, the primary target of VRT-125853 was ParE, whereas for VRT-752586 it was GyrB. DNA transformation experiments with H. influenzae and S. aureus proved that the mutations observed in gyrB resulted in decreased susceptibilities to both compounds. Novobiocin resistance-conferring mutations in S. aureus, H. influenzae, and S. pneumoniae were found in gyrB, and these mutants showed little or no cross-resistance to VRT-125853 or VRT-752586 and vice versa. Furthermore, gyrB and parE double mutations increased the MICs of VRT-125853 and VRT-752586 significantly, providing evidence of dual targeting. Spontaneous frequencies of resistance to VRT-752586 were below detectable levels (<5.2x10(-10)) for wild-type E. faecalis but were significantly elevated for strains containing single and double target-based mutations, demonstrating that dual targeting confers low levels of resistance emergence and the maintenance of susceptibility in vitro.
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PMID:Dual targeting of GyrB and ParE by a novel aminobenzimidazole class of antibacterial compounds. 1711 75

The potential for resistance development in Streptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (10(8.5) to 10(9) log10 CFU/ml) over 96 h in an in vitro pharmacodynamic (PD) model using two fluoroquinolone-susceptible isolates. The pharmacokinetics of each drug was simulated to provide a range of free areas under the concentration-time curves (fAUC) that correlated with various fluoroquinolone doses. Potential first (parC and parE)- and second-step (gyrA and gyrB) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulating fAUC/MICs of 51 and<or=60, 34 and 37, <or=82 and<or=86, and<or=24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higher fAUC/MIC ratios and recovery of topoisomerase mutations in S. pneumoniae was related to the fAUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded the fAUC/MIC resistance breakpoint against wild-type S. pneumoniae, whereas those of levofloxacin (500 and 750 mg) were associated with first- and second-step mutations. The exposure breakpoints for levofloxacin were significantly different (P<0.001) from those of the newer fluoroquinolones gatifloxacin, gemifloxacin, and moxifloxacin. Additionally, moxifloxacin breakpoints were significantly lower (P<0.002) than those of gatifloxacin. The order of resistance development determined from fAUC/MIC breakpoints was levofloxacin>gatifloxacin>moxifloxacin=gemifloxacin, which may be related to structural differences within the class.
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PMID:Fluoroquinolone resistance in Streptococcus pneumoniae: area under the concentration-time curve/MIC ratio and resistance development with gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin. 1729 40

Levofloxacin binds topoisomerase IV, whereas moxifloxacin preferentially binds DNA gyrase. Most 1st-step pneumococcal mutants have alterations in the parC gene of topoisomerase IV. Because of differential binding affinity, moxifloxacin may have superior activity against 1st-step mutants compared with levofloxacin. The purpose of this work was to compare rates and extent of bacterial killing of genetically characterized Streptococcus pneumoniae with moxifloxacin and levofloxacin. Four strains of S. pneumoniae were used: a wild type, 2 first-step parC mutants, and a pump mutant. Using an in vitro pharmacodynamic model run in duplicate, we exposed bacteria to unbound moxifloxacin and levofloxacin peaks of 2 and 4.5 mg/L, respectively, which emulated clinical dosing. Additional experiments were done in which the area under the curve (AUC)/MIC ratio of 1 agent was matched to the competing drug's clinical dose AUC/MIC ratio. Time kill curves were analyzed for rate and extent of bacterial kill and regrowth. Pre- and postexposure MIC and polymerase chain reaction (PCR) testing were done. Moxifloxacin and levofloxacin displayed similar rates and extent of bacterial kill for the wild type, efflux pump type, and parC mutant 27-1361B. Moxifloxacin initially achieved a faster rate of kill, regardless of the AUC/MIC ratio, against parC mutant 7362 (P < 0.05) but not an advantage in time to 3 log kill. Postexposure MIC values were elevated for strain 7362 in 2 moxifloxacin experiments and 1 levofloxacin experiment. Post-PCR analysis revealed new gyrA mutations for all 3 isolates. Both moxifloxacin and levofloxacin are effective against multiple strains of S. pneumoniae.
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PMID:In vitro pharmacodynamics of moxifloxacin versus levofloxacin against 4 strains of Streptococcus pneumoniae: 1 wild type, 2 first-step parC mutants, and 1 pump mutant. 1791 Sep 98

Fluoroquinolones (FQs) are broad spectrum, concentration dependent, bactericidal antimicrobials that have been commonly utilized to treat severe nosocomial infections. FQ activity is derived from their ability to inhibit DNA gyrase and topoisomerase IV; resistance has been shown to develop in target site mutations, alterations in efflux pump systems, and incorporation of plasmids. The probability of preventing emergence of resistance and achieving maximal rates of kill are best related to the ratio of free-drug in the area under the concentration-time curve (AUC) to minimum inhibitory concentration (AUC:MIC). Major dosage adjustments for FQs are not necessary in hepatic insufficiency, accumulation of extracellular fluids, and burn patients. Appropriate dosage adjustments in renal function should be taken into consideration. FQ optimization in the critically ill is a multifactorial process that should be individualized to each patient and should take into account the MIC of the pathogen, pharmacokinetic/pharmacodynamic profile of the FQ, and the patient's pathophysiological state.
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PMID:Optimizing use of quinolones in the critically ill. 1809 22


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