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Query: UNIPROT:Q29983 (MIC)
 21,138 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ceftiolene (42980RP) is a new cephalosporin with a broad antibacterial spectrum similar to cefotaxime or ceftriaxone. The characteristics of ceftiolene have been tested in a variety of assays involving various biochemical aspects of the mode of action of beta-lactam antibiotics. The affinities of ceftiolene for penicillin-binding proteins were very comparable with those of ceftriaxone and cefotaxime for Escherichia coli, and generally greater than those of latamoxef (moxalactam) for the higher molecular weight PBPs of E. coli. Enterobacter cloacae. Proteus mirabilis and Pseudomonas aeruginosa. The affinity of ceftiolene for PBP1 of Staphylococcus aureus was greater than those of cefotaxime or latamoxef, but comparable with these antibiotics for PBP3. The bacteriolytic activity of ceftiolene at defined concentrations against Gram-negative organisms was similar to that of ceftriaxone, and significantly better than that of the other third-generation cephalosporins tested. Introduction of plasmid-encoded beta-lactamases into E. coli reduced the wide variation in bacteriolytic effect of the different cephalosporins, and a significant inoculum effect was observed for the bacteriolysis. Chloramphenicol was less antagonistic against ceftiolene- or ceftriaxone-induced lysis than was observed for cefotaxime or latamoxef. Growth of Staph. aureus at low concentrations of ceftiolene caused the bacteria to become more sensitive to lysis by lysostaphin than organisms grown with cefotaxime or latamoxef under the same conditions. These observations confirm the necessity to use techniques other than routine MIC determinations to distinguish between antibiotics which would otherwise appear very similar.
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PMID:An evaluation of the bacteriolytic and biochemical properties of ceftiolene (42980RP). 639 71

The effects of pretreatment of Staphylococcus aureus with subMIC or 10 x MIC amoxycillin, cloxacillin and nafcillin on subsequent killing by bovine neutrophils or sensitivity to lysostaphin were examined in vitro, using penicillinase positive and negative strains. All penicillins increased the susceptibility of S. aureus to bovine neutrophils; with amoxycillin this was most marked with the penicillinase negative strain. Cloxacillin pretreatment was significantly more effective than nafcillin or amoxycillin in some tests and equally effective in others. The sensitivity of S. aureus to lysostaphin was increased following cloxacillin or nafcillin exposure. In a mouse model of mastitis, more cloxacillin and nafcillin-treated S. aureus (at 1/4 MIC) were killed than untreated bacteria 1 hr after infection but by 4 hr no differences were found. No differences were seen after intramammary infection with 10 x MIC penicillin-treated S. aureus. In glands with established chronic mastitis both cloxacillin and nafcillin at high doses failed to kill staphylococci. These findings indicate that prior exposure to penicillins increases staphylococcal susceptibility to killing by neutrophils but following phagocytosis, intracellular bacteria are protected from the lethal action of penicillins.
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PMID:Enhanced killing of penicillin-treated S. aureus by host defences: effects of amoxycillin, cloxacillin and nafcillin in vitro and in experimental mastitis. 689 Aug 89

In the recent clinical trials of teicoplanin therapy of endocarditis caused by Staphylococcus aureus, at least one instance of the emergence of teicoplanin-resistant strains during therapy has been reported (G.W. Kaatz, S. M. Seo, N. J. Dorman, and S. A. Lerner, J. Infect. Dis 162:103-108, 1990). We have confirmed, using conventional electrophoresis of EcoRI-digested chromosomal DNA and pulsed-field gel electrophoresis of SmaI-digested chromosomal DNA, that the resistant strain (12873) (MIC, 16 micrograms/ml) is genetically very similar to the susceptible parent (12871) (MIC, 4 micrograms/ml). Kaatz et al. were able to select spontaneous teicoplanin-resistant mutants (10(-9)), suggesting that a single gene might be involved. We have shown that the mutation is highly stable during growth in the absence of teicoplanin. Using Tn551, we have selected insertion mutants of 12873 that become teicoplanin susceptible. We have examined a number of aspects of cell wall physiology in strains 12871 and 12873 and the teicoplanin-susceptible Tn551 mutants of 12873. 12873 was more susceptible to lysostaphin lysis than 12871 and the susceptible Tn551 derivatives of 12873. Autolysis in phosphate buffer (pH 7.5) and cell wall turnover rates were similar in 12871 and 12873. An analysis of membrane proteins revealed the expression of a ca. 35-kDa protein and increased expression of both polypeptides of penicillin-binding protein (PBP) 2 (PBP2) in 12873 relative to 12871 and the Tn551 mutants of 12873. This increased expression was not related to PBP2', since both strains were susceptible to oxacillin in 2% NaCl (MIC, < or = 0.25 microgram/ml) and cellular DNA from neither strain hybridized with a specific mec gene probe. Two independent Tn551 inserts have been mapped to a ca. 117-kb SmaI fragment of the chromosome. These data suggest the possibility that the mutation resulting in resistance to teicoplanin involves the regulation of expression of both polypeptides of PBP2 and a 35-kDa membrane protein.
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PMID:Teicoplanin-resistant Staphylococcus aureus expresses a novel membrane protein and increases expression of penicillin-binding protein 2 complex. 828 29

A highly vancomycin-resistant mutant (MIC = 100 microg/ml) of Staphylococcus aureus, mutant VM, which was isolated in the laboratory by a step-pressure procedure, continued to grow and synthesize peptidoglycan in the presence of vancomycin (50 microg/ml) in the medium, but the antibiotic completely inhibited cell wall turnover and autolysis, resulting in the accumulation of cell wall material at the cell surface and inhibition of daughter cell separation. Cultures of mutant VM removed vancomycin from the growth medium through binding the antibiotic to the cell walls, from which the antibiotic could be quantitatively recovered in biologically active form. Vancomycin blocked the in vitro hydrolysis of cell walls by autolytic enzyme extracts, lysostaphin and mutanolysin. Analysis of UDP-linked peptidoglycan precursors showed no evidence for the presence of D-lactate-terminating muropeptides. While there was no significant difference in the composition of muropeptide units of mutant and parental cell walls, the peptidoglycan of VM had a significantly lower degree of cross-linkage. These observations and the results of vancomycin-binding studies suggest alterations in the structural organization of the mutant cell walls such that access of the vancomycin molecules to the sites of wall biosynthesis is blocked.
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PMID:Inhibition of cell wall turnover and autolysis by vancomycin in a highly vancomycin-resistant mutant of Staphylococcus aureus. 909 53

The mechanism of glycopeptide resistance in the genus Staphylococcus is unknown. Since these antimicrobial compounds act by binding the peptidoglycan precursor terminus, the target of transglycosylase and transpeptidase enzymes, it was hypothesized that resistance might be mediated in Staphylococcus aureus by increased production or activity of these enzymes, commonly called penicillin-binding proteins (PBPs). To evaluate this possibility, glycopeptide-resistant mutants were prepared by passage of several clinical isolates of this species in nutrient broth containing successively increasing concentrations of the glycopeptide vancomycin or teicoplanin. Decreased coagulase activity and increased resistance to lysostaphin were uniformly present in the vancomycin-resistant mutants. Peptidoglycan cross-linking increased in one resistant isolate and decreased in two resistant isolates. The amounts of radioactive penicillin that bound to each PBP in susceptible and resistant strains were compared; PBP2 production was also evaluated by Western blotting. Increased penicillin labeling and production of PBP2 were found in all resistant derivatives selected by either vancomycin or teicoplanin. Moreover, the increase in PBP2 penicillin labeling occurred early in a series of vancomycin-selected derivatives and was strongly correlated (r > 0.9) with the increase in vancomycin and teicoplanin MIC. An increase in penicillin labeling also occurred, variably, in PBP1, PBP3, and/or PBP4. These data demonstrate a strong correlation between resistance to glycopeptides and increased PBP activity and/or production in S. aureus. Such an increase could allow PBPs to better compete with glycopeptides for the peptidoglycan precursor.
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PMID:Increased production of penicillin-binding protein 2, increased detection of other penicillin-binding proteins, and decreased coagulase activity associated with glycopeptide resistance in Staphylococcus aureus. 925 62

The recent identification of glycopeptide intermediate-resistant Staphylococcus aureus (GISA) clinical isolates has provided an opportunity to assess the stability of the glycopeptide resistance phenotype by nonselective serial passage and to evaluate reversion-associated cell surface changes. Three GISA isolates from the United States (MIC of vancomycin = 8 microg/ml) and two from Japan (MICs of vancomycin = 8 and 2 microg/ml) were passaged daily on nutrient agar with or without vancomycin supplementation. After 15 days of passage on nonselective medium, vancomycin- and teicoplanin-susceptible revertants were obtained from each GISA isolate as determined by broth dilution MIC. Revertant isolates were compared with parent isolates for changes in vancomycin heteroresistance, capsule production, hemolysis phenotype, coagulase activity, and lysostaphin susceptibility. Several revertants lost the subpopulations with intermediate vancomycin resistance, whereas two revertants maintained them. Furthermore, although all of the parent GISA isolates produced capsule type 5 (CP5), all but one revertant tested no longer produced CP5. In contrast, passage on medium containing vancomycin yielded isolates that were still intermediately resistant to vancomycin, had no decrease in the MIC of teicoplanin, and produced detectable CP5. No consistent changes in the revertants in hemolysis phenotype, lysostaphin susceptibility, or coagulase activities were discerned. These data indicate that the vancomycin resistance phenotype is unstable in clinical GISA isolates. Reversion of the vancomycin resistance phenotype might explain the difficulty in isolating vancomycin-resistant clinical isolates from the blood of patients who fail vancomycin therapy and, possibly, may account for some of the difficulties in identifying GISA isolates in the clinical laboratory.
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PMID:Reversion of the glycopeptide resistance phenotype in Staphylococcus aureus clinical isolates. 1063 49

A series of 12 Staphylococcus aureus strains of various genetic backgrounds, methicillin resistance levels, and autolytic activities were subjected to selection for the glycopeptide-intermediate S. aureus (GISA) susceptibility phenotype on increasing concentrations of vancomycin. Six strains acquired the phenotype rapidly, two did so slowly, and four failed to do so. The vancomycin MICs for the GISA strains ranged from 4 to 16 microg/ml, were stable to 20 nonselective passages, and expressed resistance homogeneously. Neither ease of acquisition of the GISA phenotype nor the MIC attained correlated with methicillin resistance hetero- versus homogeneity or autolytic deficiency or sufficiency. Oxacillin MICs were generally unchanged between parent and GISA strains, although the mec members of both isogenic methicillin-susceptible and methicillin-resistant pairs acquired the GISA phenotype more rapidly and to higher MICs than did their susceptible counterparts. Transmission electron microscopy revealed that the GISA strains appeared normal in the absence of vancomycin but had thickened and diffuse cell walls when grown with vancomycin at one-half the MIC. Common features among GISAs were reduced doubling times, decreased lysostaphin susceptibilities, and reduced whole-cell and zymographic autolytic activities in the absence of vancomycin. This, with surface hydrophobicity differences, indicated that even in the absence of vancomycin the GISA cell walls differed from those of the parents. Autolytic activities were further reduced by the inclusion of vancomycin in whole-cell and zymographic studies. The six least vancomycin-susceptible GISA strains exhibited an increased capacity to remove vancomycin from the medium versus their parent lines. This study suggests that while some elements of the GISA phenotype are strain specific, many are common to the phenotype although their expression is influenced by genetic background. GISA strains with similar glycopeptide MICs may express individual components of the phenotype to different extents.
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PMID:Characterization of passage-selected vancomycin-resistant Staphylococcus aureus strains of diverse parental backgrounds. 1063 53

Recently, Staphylococcus aureus strains with intermediate resistance to vancomycin, the antibiotic of last resort, have been described. Multiple changes in peptidoglycan turnover and structure contribute to the resistance phenotype. Here, we describe that structural changes of teichoic acids in the cell envelope have a considerable influence on the susceptibility to vancomycin and other glycopeptides. S. aureus cells lacking D-alanine esters in teichoic acids exhibited an at least threefold-increased sensitivity to glycopeptide antibiotics. Furthermore, the autolytic activity of the D-alanine mutant was reduced compared to the wild-type, and the mutant was more susceptible to the staphylolytic enzyme lysostaphin. Vancomycin inhibited autolysis at very high concentrations but neither in the wild-type nor in the mutant was the autolytic activity influenced in the range of the MIC. Mutant cells had a considerably higher capacity to bind vancomycin.
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PMID:The D-alanine residues of Staphylococcus aureus teichoic acids alter the susceptibility to vancomycin and the activity of autolytic enzymes. 1099 69

Glycopeptide resistance in Staphylococcus aureus is poorly understood. The diversity of change documented in cell walls of clinical glycopeptide-intermediate S. aureus (GISA) isolates is evidence that a single genetic or biochemical change cannot account for resistance in all isolates described to date. Therefore, identification of new GISA clinical isolates provides an opportunity to gain insight into the range of adaptive strategies employed by staphylococci to survive in the presence of glycopeptides. In April 1999, a GISA isolate was obtained from the blood of a 63-year-old dialysis patient in Illinois. This isolate was one of six clonally identical MRSA isolates (A-F) serially obtained from the blood of this patient who was receiving vancomycin therapy. All isolates were resistant to oxacillin (MIC > 256 mg/L). The initial isolate had an MIC of vancomycin of 1 mg/L. However, the presence of a subpopulation that could grow in the presence of 5 mg/L of vancomycin indicated that this isolate was predisposed to the acquisition of the GISA phenotype (MIC of vancomycin 10-12 mg/L), which occurred 13 days later, associated with an increased MIC of the endopeptidase lysostaphin and slightly increased cell wall thickness. The first and last isolates in the series, A and F, resisted killing when incubated in vancomycin 2 mg/L, resisted autolysis when incubated in Triton X-100 and had a decreased expression of a c. 116 kDa autolytic band, properties that were different from glycopeptide-susceptible control isolates. Lysostaphin resistance was not accompanied by alterations in the peptidoglycan pentaglycine cross-bridge or a decrease in oxacillin MIC. These data, when taken together with the demonstration of increased cross-linking in isolate F compared with isolate A, demonstrate that vancomycin resistance in these isolates probably occurred by a mechanism different from that of other GISA isolates described to date.
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PMID:Development of vancomycin and lysostaphin resistance in a methicillin-resistant Staphylococcus aureus isolate. 1167 50

The anterior nares are a primary ecologic niche for Staphylococcus aureus, and nasal colonization by this opportunistic pathogen increases the risk of development of S. aureus infection. Clearance of S. aureus nasal colonization greatly reduces this risk. Mupirocin ointment is the current standard of care for clearance of S. aureus nasal colonization, but resistance to this antibiotic is emerging. Lysostaphin is a glycylglycine endopeptidase which specifically cleaves the cross-linking pentaglycine bridges in the cell walls of staphylococci. Lysostaphin is extremely staphylocidal (MIC at which 90% of isolates are inhibited, 0.001 to 0.064 micro g/ml) and rapidly lyses both actively growing and quiescent S. aureus. This study demonstrates that a single application of 0.5% lysostaphin (actual dose, approximately 150 micro g of lysostaphin), formulated in a petrolatum-based cream, dramatically reduces S. aureus nasal colonization in 100% of animals tested and eradicates S. aureus nasal colonization in 93% of animals in a cotton rat model. A single dose of lysostaphin cream is more effective than a single dose of mupirocin ointment in eradicating S. aureus nasal colonization in this animal model. The lantibiotic peptide nisin, which has potent in vitro antistaphylococcal activity, was ineffective in reducing staphylococcal nasal carriage in this model. Nasal colonization was not reduced after three treatments with 5% nisin ( approximately 1,500 micro g/dose) in any of the treated animals. Lysostaphin formulated in cream may prove to be a superior alternative to mupirocin ointment for clearance of S. aureus nasal colonization.
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PMID:Lysostaphin cream eradicates Staphylococcus aureus nasal colonization in a cotton rat model. 1270 27


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