2,044 results on '"Glycopeptides pharmacology"'
Search Results
202. Use of in vitro vancomycin testing results to predict susceptibility to oritavancin, a new long-acting lipoglycopeptide.
- Author
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Jones RN, Turnidge JD, Moeck G, Arhin FF, and Mendes RE
- Subjects
- Enterococcus drug effects, Gram-Positive Bacteria drug effects, Lipoglycopeptides, Microbial Sensitivity Tests, Predictive Value of Tests, Reference Standards, Staphylococcus aureus drug effects, Streptococcus drug effects, Vancomycin Resistance drug effects, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial drug effects, Glycopeptides pharmacology, Vancomycin pharmacology
- Abstract
Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 μg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 μg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
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- 2015
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203. Modulation of TNF-α, TNF-α receptors and IL-6 after treatment with AM3 in professional cyclists.
- Author
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Córdova A, Sureda A, Pons A, and Alvarez-Mon M
- Subjects
- Adult, Bicycling, Double-Blind Method, Humans, Male, Young Adult, Adjuvants, Immunologic pharmacology, Athletes, Calcium Phosphates pharmacology, Glycopeptides pharmacology, Interleukin-6 blood, Receptors, Tumor Necrosis Factor blood, Tumor Necrosis Factor-alpha blood
- Abstract
Aim: Changes in IL-6, TNF-α, and TNF-α receptors - sTNFRI and sTNFRII - were evaluated in a group of professional cyclists treated with immunomodulator AM3 (Inmunoferón®) for 6 months of training and competition., Methods: Sixteen male professional cyclists with a similar training program participated in the study which was designed as a randomized, placebo-controlled, double-blind clinical trial. Venous blood samples were collected in basal conditions, before beginning the supplementation program, and after 90 and 180 days of training and competition season., Results: No significant differences in biochemical parameters or in IL-6 were evidenced between placebo and AM3-treated groups throughout the study. Plasma TNF-α levels significantly decreased (P<0.05) after 90 days of training in the AM3 treated group. TNF-α receptors increased during training season in both placebo and AM3 treated groups, although the increase was significantly higher (P<0.05) in the AM3 group with respect to the placebo group., Conclusion: The changes produced by regular training and competition were modified throughout the season by AM3 treatment which could reduce the inflammatory response to excessive exercise.
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- 2015
204. Anti-biofilm activity and synergism of novel thiazole compounds with glycopeptide antibiotics against multidrug-resistant staphylococci.
- Author
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Mohammad H, Mayhoub AS, Cushman M, and Seleem MN
- Subjects
- Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents chemical synthesis, Drug Resistance, Multiple, Bacterial, Drug Synergism, Glycopeptides administration & dosage, Humans, Methicillin-Resistant Staphylococcus aureus drug effects, Methicillin-Resistant Staphylococcus aureus isolation & purification, Microbial Sensitivity Tests, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Staphylococcus aureus drug effects, Staphylococcus aureus isolation & purification, Staphylococcus epidermidis drug effects, Thiazoles administration & dosage, Thiazoles chemical synthesis, Vancomycin administration & dosage, Vancomycin pharmacology, Vancomycin Resistance, Anti-Bacterial Agents pharmacology, Biofilms drug effects, Glycopeptides pharmacology, Thiazoles pharmacology
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infections are a leading cause of death among all fatalities caused by antibiotic-resistant bacteria. With the rise of increasing resistance to current antibiotics, new antimicrobials and treatment strategies are urgently needed. Thiazole compounds have been shown to possess potent antimicrobial activity. A lead thiazole 1 and a potent derivative 2 were synthesized and their activity in combination with glycopeptide antibiotics was determined against an array of MRSA and vancomycin-resistant S. aureus (VRSA) clinical isolates. In addition, the anti-biofilm activity of the novel thiazoles was investigated against S. epidermidis. Compound 2 behaved synergistically with vancomycin against MRSA and was able to resensitize VRSA to vancomycin, reducing its MIC by 512-fold in two strains. In addition, both thiazole compounds were superior to vancomycin in significantly reducing S. epidermidis biofilm mass. Collectively, the results obtained demonstrate that compounds 1 and 2 possess potent antimicrobial activity alone or in combination with vancomycin against multidrug-resistant staphylococci and show potential for use in disrupting staphylococcal biofilm.
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- 2015
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205. Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo.
- Author
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Krishnamurthy VR, Sardar MY, Ying Y, Song X, Haller C, Dai E, Wang X, Hanjaya-Putra D, Sun L, Morikis V, Simon SI, Woods RJ, Cummings RD, and Chaikof EL
- Subjects
- Animals, Blood Platelets drug effects, Blood Platelets metabolism, Cell Aggregation drug effects, Cell Line, E-Selectin metabolism, Flow Cytometry, Humans, In Vitro Techniques, L-Selectin metabolism, Leukocytes drug effects, Leukocytes metabolism, Male, Mice, Molecular Dynamics Simulation, Monocytes metabolism, Muscle, Skeletal metabolism, Neutrophils metabolism, P-Selectin metabolism, Protein Binding, Cell Adhesion drug effects, Glycopeptides pharmacology, Membrane Glycoproteins pharmacology, Monocytes drug effects, Muscle, Skeletal drug effects, Neutrophils drug effects, P-Selectin antagonists & inhibitors
- Abstract
Blockade of P-selectin (P-sel)/PSGL-1 interactions holds significant potential for treatment of disorders of innate immunity, thrombosis and cancer. Current inhibitors remain limited due to low binding affinity or by the recognized disadvantages inherent to chronic administration of antibody therapeutics. Here we report an efficient approach for generating glycosulfopeptide mimics of N-terminal PSGL-1 through development of a stereoselective route for multi-gram scale synthesis of the C2 O-glycan building block and replacement of hydrolytically labile tyrosine sulfates with isosteric sulfonate analogues. Library screening afforded a compound of exceptional stability, GSnP-6, that binds to human P-sel with nanomolar affinity (Kd~22 nM). Molecular dynamics simulation defines the origin of this affinity in terms of a number of critical structural contributions. GSnP-6 potently blocks P-sel/PSGL-1 interactions in vitro and in vivo and represents a promising candidate for the treatment of diseases driven by acute and chronic inflammation.
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- 2015
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206. Structure diversification of vancomycin through peptide-catalyzed, site-selective lipidation: a catalysis-based approach to combat glycopeptide-resistant pathogens.
- Author
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Yoganathan S and Miller SJ
- Subjects
- Anti-Bacterial Agents chemistry, Catalysis, Crystallography, X-Ray, Glycopeptides chemistry, Microbial Sensitivity Tests, Molecular Conformation, Molecular Structure, Structure-Activity Relationship, Vancomycin chemistry, Anti-Bacterial Agents pharmacology, Enterococcus drug effects, Glycopeptides pharmacology, Lipids chemistry, Lipoylation, Methicillin-Resistant Staphylococcus aureus drug effects, Vancomycin pharmacology, Vancomycin Resistance drug effects
- Abstract
The emergence of antibiotic-resistant infections highlights the need for novel antibiotic leads, perhaps with a broader spectrum of activity. Herein, we disclose a semisynthetic, catalytic approach for structure diversification of vancomycin. We have identified three unique peptide catalysts that exhibit site-selectivity for the lipidation of the aliphatic hydroxyls on vancomycin, generating three new derivatives 9a, 9b, and 9c. Incorporation of lipid chains into the vancomycin scaffold provides promising improvement of its bioactivity against vancomycin-resistant enterococci (Van A and Van B phenotypes of VRE). The MICs for 9a, 9b, and 9c against MRSA and VRE (Van B phenotype) range from 0.12 to 0.25 μg/mL. We have also performed a structure-activity relationship (SAR) study to investigate the effect of lipid chain length at the newly accessible G4-OH derivatization site.
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- 2015
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207. Understanding the importance of glycosylated threonine and stereospecific action of Drosocin, a Proline rich antimicrobial peptide.
- Author
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Lele DS, Talat S, Kumari S, Srivastava N, and Kaur KJ
- Subjects
- Dose-Response Relationship, Drug, Glycosylation, Gram-Negative Bacteria drug effects, Microbial Sensitivity Tests, Stereoisomerism, Structure-Activity Relationship, Antimicrobial Cationic Peptides chemistry, Antimicrobial Cationic Peptides pharmacology, Glycopeptides chemistry, Glycopeptides pharmacology, Proline chemistry, Threonine chemistry, Threonine pharmacology
- Abstract
Glycosylation is an essential post-translational modification for few antimicrobial peptides of Proline rich class. In the present study we have shown the importance of Thr glycosylation over Ser glycosylation in Drosocin. Difference of a methyl group makes glycosylated-Thr preferred over glycosylated-Ser and renders higher activity to the peptide, probably due to the rigid conformation provided by the glycosylated-Thr. The structural rigidity provided by glycosylated-Thr to Drosocin backbone was mimicked by substituting glycosylated-Thr11, Ser7 and Ser12 with Pro residues. The designed non-glycosylated analogue, P(7)P(11)P(12)-Drosocin, exhibited functional and structural properties similar to that of the native monoglycosylated peptide. The functional importance of stereospecificity of amino acids and sugar was further explored. Interestingly, (all D) p(7)p(11)p(12)-Drosocin failed to exhibit antimicrobial activity but had comparable binding affinity to DnaK, one of the proposed targets for Proline rich class of antibacterial peptides, as that of its L counterpart. However, Drosocin containing either L or D enantiomeric sugar, displayed antimicrobial activity and binding affinity to bacterial heat shock protein, DnaK. The flow cytometry (FACS) experiments revealed the internalization of Drosocins bearing enantiomeric sugars and P(7)P(11)P(12)-Drosocin but not of its d-enantiomer into bacteria suggesting the importance of stereospecificity of amino acids for membrane entry. Once internalized both enantiomeric peptides may behave similarly. This assumption was corroborated by in vitro activity of (all D) p(7)p(11)p(12)-Drosocin in cell free assay where it abrogated transcription/translation pathway similar to l-enantiomer but could not inhibit the same in whole cell assay. These research findings provide insights into the mode of action of Proline rich class of antibacterial peptides and guidelines for designing functionally equivalent non-glycosylated analogues of glycosylated antibacterial peptides., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
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- 2015
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208. Multiple colonization with highly resistant bacteria: carbapenemase-producing Enterobacteriaceae, carbapenemase-producing Pseudomonas aeruginosa, carbapenemase-producing Acinetobacter baumannii, and glycopeptide-resistant Enterococcus faecium.
- Author
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Girlich D, Nordmann P, Lécuyer H, Berche P, Marmorat-Khuong A, Gros I, Cuzon G, and Dortet L
- Subjects
- Adult, Aged, Bacteria classification, Bacteria drug effects, Bacteria enzymology, Coinfection microbiology, Female, Humans, Male, Anti-Bacterial Agents pharmacology, Bacteria isolation & purification, Bacterial Infections microbiology, Bacterial Proteins metabolism, Carrier State microbiology, Drug Resistance, Multiple, Bacterial, Glycopeptides pharmacology, beta-Lactamases metabolism
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- 2015
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209. Improved production of sublancin via introduction of three characteristic promoters into operon clusters responsible for this novel distinct glycopeptide biosynthesis.
- Author
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Ji S, Li W, Baloch AR, Wang M, and Cao B
- Subjects
- Bacillus subtilis genetics, Bacillus subtilis metabolism, Bacteria classification, Bacteria drug effects, Bacteria growth & development, Bacterial Proteins metabolism, Bacteriocins chemistry, Bacteriocins pharmacology, Cell Survival drug effects, Circular Dichroism, Culture Media, Conditioned metabolism, Glycopeptides chemistry, Glycopeptides pharmacology, HT29 Cells, Humans, Hydrogen-Ion Concentration, Metabolic Engineering methods, Microbial Sensitivity Tests, Molecular Weight, Protein Stability, Spectrometry, Mass, Electrospray Ionization, Temperature, Bacterial Proteins genetics, Bacteriocins biosynthesis, Glycopeptides biosynthesis, Operon genetics, Promoter Regions, Genetic genetics
- Abstract
Background: Sublancin is a novel and distinct antimicrobial glycopeptide that can be used as an alternative to conventional antibiotics. The reported production of sublancin by Bacillus subtilis 168 is poor because transcriptional regulatory circuit of sunA, a gene that encodes presublancin, is complex and difficult to control., Results: A strong inducible and easy to control vegetative σA promoter of Pglv was introduced to replace that of sunA in situ in B. subtilis 1A747 [SPβc, prototroph, the derivative of B. subtilis 168 (trpC2)]. Meanwhile, other two strong promoters of P43 and PluxS were respectively placed before sunI and sunT-bdbA-sunS-bdbB, encoding five functional proteins that involved in the biosynthesis of mature sublancin. 642 mg sublancin was obtained from 1 L culture supernatant of recombinant B. subtilis 1A747 strains. Analysises of electrospray ionization mass spectrometry and circular dichroism spectrum showed that mature sublancin had a molecular weight of 3877.642 Da and displayed a α-helical conformation that are consistent with reported results. In addition, the mature sublancin was proved to be a potent antimicrobial glycopeptide with broad activity spectrum, moderate cytotoxicity and good conditional stability under high temperature, extreme pH and protease-rich environments, thus showing its potential for clinical applications., Conclusions: Our present findings suggest that recombinant B. subtilis 1A747 strains can effectively and efficiently biosynthesize mature sublancin. The replacement of native promoters provides an extra method for production improvement of some other complicated peptides such as nisin and subtilin.
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- 2015
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210. Glycosylated enfuvirtide: a long-lasting glycopeptide with potent anti-HIV activity.
- Author
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Cheng S, Chang X, Wang Y, Gao GF, Shao Y, Ma L, and Li X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, Enfuvirtide, Glycopeptides chemical synthesis, Glycopeptides chemistry, Glycosylation, HIV Envelope Protein gp41 chemical synthesis, HIV Envelope Protein gp41 chemistry, Microbial Sensitivity Tests, Molecular Structure, Peptide Fragments chemical synthesis, Peptide Fragments chemistry, Structure-Activity Relationship, Anti-HIV Agents pharmacology, Glycopeptides pharmacology, HIV drug effects, HIV Envelope Protein gp41 pharmacology, Peptide Fragments pharmacology
- Abstract
Many peptide-based therapeutics have short circulatory half-lives. We report here that the pharmacokinetics of an anti-HIV peptide drug enfuvirtide (ENF) can be dramatically improved by a chemical glycosylation approach. A set of glycosylated ENFs with varying glycosylation sites and glycan structures were synthesized. Among these, a sialic acid-introduced peptide (SL-ENF) demonstrated a 15-fold extended half-life in rats relative to ENF (T1/2: 23.1 vs 1.5 h), and its antiviral potency was comparable to that of ENF (EC50: 2 vs 3 nM). SL-ENF bound to a functional fragment of the HIV fusogenic protein gp41 and formed complexes with high affinity and α-helicity, revealing the mechanism behind its potent antiviral activity. Because it is widely accepted in biology that glycosylation protects proteins from denaturation and proteases, our approach may be useful for the development of novel protein and peptide drugs with enhanced pharmaceutical properties.
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- 2015
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211. Isolation, purification, and characterization of avian antimicrobial glycopeptide from the posterior salivary gland of Sepia pharaonis.
- Author
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Karthik R, Saravanan R, Ebenezar KK, and Sivamalai T
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Chemical Fractionation, Chickens, Chromatography, Gel, Chromatography, High Pressure Liquid, Chromatography, Reverse-Phase, Circular Dichroism, Electrophoresis, Polyacrylamide Gel, Glycopeptides chemistry, Microbial Sensitivity Tests, Molecular Weight, Spectrophotometry, Infrared, Time Factors, Anti-Bacterial Agents isolation & purification, Anti-Bacterial Agents pharmacology, Glycopeptides isolation & purification, Glycopeptides pharmacology, Salivary Glands chemistry, Sepia chemistry
- Abstract
A proteinaceous glycopeptide was isolated from the posterior salivary gland (PSG) of Sepia pharaonis by gel (Sephadex G-100) filtration chromatography and purified by reversed-phase high-performance liquid chromatography (RP-HPLC). Among the collected fractions, fraction 12 showed a retention time (RT) of 31 min. The total protein and neutral sugar contents of the purified glycopeptide were recorded as 68.14 and 2.95 mg, respectively. The molecular weight of the purified glycopeptide was found to be ~50 kDa. The infrared (IR) and circular dichroism (CD) spectroscopy confirmed the presence of peptide and secondary structure in the purified glycopeptide. The antibacterial activity of the purified glycopeptide against avian bacterial strains was also determined. Gas chromatography-mass spectrometry (GC-MS) of the purified glycopeptide revealed the likely compounds for the antibacterial activity such as 22, 23-dibromostigmasterol acetate, 3-methyl 2-(2-oxypropyl) furan, and 2,4,4-trimethyl-3-hydroxymethyl-5A-(3-methyl-but-2-enyl)-cyclohexene. These three compounds found in the purified glycopeptide could be responsible for the antibacterial activity against the avian pathogens. The results of this study suggest that the purified glycopeptide from the PSG of S. pharaonis could be an antibacterial agent against avian bacterial pathogens.
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- 2015
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212. Structural variations of the cell wall precursor lipid II and their influence on binding and activity of the lipoglycopeptide antibiotic oritavancin.
- Author
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Münch D, Engels I, Müller A, Reder-Christ K, Falkenstein-Paul H, Bierbaum G, Grein F, Bendas G, Sahl HG, and Schneider T
- Subjects
- Enterococcus faecium chemistry, Lipoglycopeptides, Microbial Sensitivity Tests, Staphylococcus aureus drug effects, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Glycopeptides chemistry, Glycopeptides pharmacology
- Abstract
Oritavancin is a semisynthetic derivative of the glycopeptide antibiotic chloroeremomycin with activity against Gram-positive pathogens, including vancomycin-resistant staphylococci and enterococci. Compared to vancomycin, oritavancin is characterized by the presence of two additional residues, a hydrophobic 4'-chlorobiphenyl methyl moiety and a 4-epi-vancosamine substituent, which is also present in chloroeremomycin. Here, we show that oritavancin and its des-N-methylleucyl variant (des-oritavancin) effectively inhibit lipid I- and lipid II-consuming peptidoglycan biosynthesis reactions in vitro. In contrast to that for vancomycin, the binding affinity of oritavancin to the cell wall precursor lipid II appears to involve, in addition to the D-Ala-D-Ala terminus, other species-specific binding sites of the lipid II molecule, i.e., the crossbridge and D-isoglutamine in position 2 of the lipid II stem peptide, both characteristic for a number of Gram-positive pathogens, including staphylococci and enterococci. Using purified lipid II and modified lipid II variants, we studied the impact of these modifications on the binding of oritavancin and compared it to those of vancomycin, chloroeremomycin, and des-oritavancin. Analysis of the binding parameters revealed that additional intramolecular interactions of oritavancin with the peptidoglycan precursor appear to compensate for the loss of a crucial hydrogen bond in vancomycin-resistant strains, resulting in enhanced binding affinity. Augmenting previous findings, we show that amidation of the lipid II stem peptide predominantly accounts for the increased binding of oritavancin to the modified intermediates ending in D-Ala-D-Lac. Corroborating our conclusions, we further provide biochemical evidence for the phenomenon of the antagonistic effects of mecA and vanA resistance determinants in Staphylococcus aureus, thus partially explaining the low frequency of methicillin-resistant S. aureus (MRSA) acquiring high-level vancomycin resistance., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
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- 2015
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213. Activity of oritavancin against Gram-positive clinical isolates responsible for documented skin and soft-tissue infections in European and US hospitals (2010-13).
- Author
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Mendes RE, Farrell DJ, Sader HS, Flamm RK, and Jones RN
- Subjects
- Cross Infection epidemiology, Drug Resistance, Bacterial, Europe epidemiology, Gram-Positive Bacteria classification, Gram-Positive Bacteria isolation & purification, Gram-Positive Bacterial Infections epidemiology, Humans, Lipoglycopeptides, Microbial Sensitivity Tests, Public Health Surveillance, Skin Diseases, Bacterial epidemiology, Soft Tissue Infections epidemiology, United States epidemiology, Anti-Bacterial Agents pharmacology, Cross Infection microbiology, Glycopeptides pharmacology, Gram-Positive Bacteria drug effects, Gram-Positive Bacterial Infections microbiology, Skin Diseases, Bacterial microbiology, Soft Tissue Infections microbiology
- Abstract
Objectives: To assess oritavancin activity in vitro against clinically relevant Gram-positive pathogens causing skin and soft-tissue infections (SSTIs) in European and US hospitals., Methods: 13 262 consecutive and unique isolates deemed to be responsible for SSTIs were included. Isolates originated from 36 and 27 institutions in Europe (Israel included) and the USA, respectively, between 2010 and 2013., Results: Oritavancin (98.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.03, 0.03 and 0.06 mg/L, respectively, for Staphylococcus aureus. CoNS from the USA (MIC50, 0.015 mg/L) demonstrated an MIC50 value of oritavancin slightly lower than those from Europe (MIC50, 0.03 mg/L). Overall, vancomycin-resistant (VanA-phenotype) Enterococcus faecalis had oritavancin MICs (MIC50/90, 0.25/0.5 mg/L) that were 16-fold higher than those obtained for vancomycin-susceptible isolates (MIC50/90, 0.015/0.03 mg/L; 99.2%-99.8% susceptible); nevertheless, oritavancin inhibited all VanA E. faecalis at ≤0.5 mg/L. Equivalent oritavancin MICs (MIC50/90, 0.004/0.008 mg/L) were noted for all VanB and vancomycin-susceptible Enterococcus faecium, while higher MICs (MIC50/90, 0.03/0.12 mg/L) were obtained for VanA strains. Oritavancin had low MICs against the overall populations of Streptococcus pyogenes (MIC50/90, 0.03/0.12 mg/L; 98.4%-98.6% susceptible), Streptococcus agalactiae (MIC50/90, 0.03/0.06 mg/L; 97.9%-98.0% susceptible) and the Streptococcus anginosus group (MIC50/90, 0.008/0.015 mg/L; 100.0% susceptible), with slightly higher MICs for Streptococcus dysgalactiae (MIC50/90, 0.06/0.25 mg/L; ≥98.3% susceptible)., Conclusions: Oritavancin had potent activity in vitro against this contemporary collection of European and US isolates causing SSTIs. These results describe oritavancin activity against Gram-positive pathogens collected shortly prior to its regulatory approval in the USA., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
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- 2015
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214. Effect of three peptidase inhibitors on antinociceptive potential and toxicity with intracerebroventricular administration of dynorphin A (1-17) or (1-13) in the rat.
- Author
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Ajimi J, Yoshikawa M, Takahashi S, Miura M, Tsukamoto H, Kawaguchi M, Kobayashi H, and Suzuki T
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- Analgesics, Opioid administration & dosage, Analgesics, Opioid pharmacology, Animals, Brain Chemistry drug effects, Captopril administration & dosage, Captopril pharmacology, Dose-Response Relationship, Drug, Dynorphins administration & dosage, Dynorphins pharmacology, Glycopeptides administration & dosage, Glycopeptides pharmacology, Injections, Intraventricular, Male, Pain Measurement drug effects, Peptides administration & dosage, Peptides pharmacology, Rats, Rats, Wistar, Receptors, Opioid drug effects, Analgesics adverse effects, Analgesics pharmacology, Analgesics, Opioid toxicity, Dynorphins toxicity, Protease Inhibitors pharmacology
- Abstract
Purpose: The N- and C-terminal regions of dynorphin (Dyn) A (1-17) activate opioid and N-methyl-D-aspartate receptors, respectively. Earlier studies demonstrated that Dyn-converting enzyme cleaved Dyn A (1-17) mainly at the Arg(6)-Arg(7) bond, resulting in the production of N- and C-terminal region peptide fragments, and that this enzyme was not inhibited by a mixture of the three peptidase inhibitors (PIs) amastatin (A), captopril (C), and phosphoramidon (P). The purpose of the present study was to evaluate antinociceptive potential and toxicity with intracerebroventricular administration of Dyn A (1-17) or (1-13) under pretreatment with a mixture of A, C, and P and/or Dyn-converting enzyme inhibitor (p-hydroxymercuribenzoate)., Methods: Peptide fragments from Dyn A (1-17) following incubation with membrane preparation under pretreatment with a mixture of the three PIs was identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS). Infusion of drugs and peptides into the third ventricle in rats was performed via indwelling cannulae. Induction of antinociception and toxicity by Dyn A (1-17), Dyn A (1-13), Dyn A (1-6), or Dyn A (7-17) were determined by the tail-flick test and induction of barrel rotation, respectively. The effects of the PIs on antinociception and toxicity were evaluated by a dose-response study and a comparison of differences among various combinations of Dyn A (1-17) or Dyn A (1-13) and the three PIs and p-hydroxymercuribenzoate., Results: MALDI-TOF-MS analysis identified Dyn A (1-6) and Dyn A (1-10) fragments as products following incubation of Dyn A (1-17) with membrane preparation of rat midbrain under pretreatment with a mixture of the three PIs. Pretreatment with a mixture of the three PIs produced an approximately 30-fold augmentation in antinociception induced by low-dose intracerebroventricular administration of Dyn A (1-17) or (1-13) in a μ-, δ- and κ-opioid receptor antagonist-reversible manner, but without signs of toxicity such as barrel rotation in the rat. Dyn A (1-17)-induced antinociception and toxicity was greater than that of Dyn A (1-6), Dyn A (1-13), or Dyn A (7-17) at the same dose. Dyn A (1-17)-induced antinociception and toxicity under pretreatment with various combinations of the three PIs and p-hydroxymercuribenzoate was greater than that with a mixture of the three PIs alone., Conclusion: These findings suggest that administration of a mixture of the three PIs increases Dyn A (1-17)- or (1-13)-induced antinociception under physiological conditions without toxicity.
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- 2015
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215. Characterization of immunomodulatory activities of honey glycoproteins and glycopeptides.
- Author
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Mesaik MA, Dastagir N, Uddin N, Rehman K, and Azim MK
- Subjects
- Animals, Cell Line, Chromatography, Gel, Glycopeptides isolation & purification, Glycoproteins isolation & purification, Humans, Macrophage Activation drug effects, Macrophages drug effects, Macrophages immunology, Mice, Monocytes immunology, Neutrophil Activation drug effects, Neutrophils drug effects, Neutrophils immunology, Nitric Oxide biosynthesis, Phagocytosis drug effects, Reactive Oxygen Species antagonists & inhibitors, Reactive Oxygen Species metabolism, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha biosynthesis, Ziziphus, Zymosan pharmacology, Glycopeptides pharmacology, Glycoproteins pharmacology, Honey analysis, Immunologic Factors pharmacology
- Abstract
Recent evidence suggests an important role for natural honey in modulating immune response. To identify active components responsible, this study investigated the immunomodulatory properties of glycoproteins and glycopeptides fractionated from Ziziphus honey. Honey proteins/peptides were fractionated by size exclusion chromatography into five peaks with molecular masses in the range of 2-450 kDa. The fractionated proteins exhibited potent, concentration-dependent inhibition of reactive oxygen species production in zymosan-activated human neutrophils (IC50 = 6-14 ng/mL) and murine macrophages (IC50 = 2-9 ng/mL). Honey proteins significantly suppressed the nitric oxide production by LPS-activated murine macrophages (IC50 = 96-450 ng/mL). Moreover, honey proteins inhibited the phagocytosis latex bead macrophages. The production of pro-inflammatory cytokines IL-1β and TNF-α by human monocytic cell line in the presence of honey proteins was analyzed. Honey proteins did not affect the production of IL-1β; however, TNF-α production was significantly suppressed. These findings indicated that honey glycoproteins and glycopeptides significantly interfere with molecules of the innate immune system.
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- 2015
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216. Antigiardial activity of glycoproteins and glycopeptides from Ziziphus honey.
- Author
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Mohammed SE, Kabashi AS, Koko WS, and Azim MK
- Subjects
- Antiprotozoal Agents chemistry, Antiprotozoal Agents pharmacology, Giardia lamblia drug effects, Glycopeptides pharmacology, Glycoproteins pharmacology, Honey, Ziziphus chemistry
- Abstract
Natural honey contains an array of glycoproteins, proteoglycans and glycopeptides. Size-exclusion chromatography fractionated Ziziphus honey proteins into five peaks with molecular masses in the range from 10 to >200 kDa. The fractionated proteins exhibited in vitro activities against Giardia lamblia with IC50 values ≤ 25 μg/mL. Results indicated that honey proteins were more active as antiprotozoal agents than metronidazole. This study indicated the potential of honey proteins and peptides as novel antigiardial agents.
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- 2015
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217. A perspective on the next generation of antibacterial agents derived by manipulation of natural products.
- Author
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Brown P and Dawson MJ
- Subjects
- Aminoglycosides pharmacology, Glycopeptides pharmacology, Ketolides pharmacology, Tetracyclines pharmacology, Anti-Bacterial Agents pharmacology, Biological Products pharmacology
- Abstract
Natural products have been a major source of anti-infective drugs for many decades. With urgent need for new antibacterial agents to combat drug-resistant bacteria, the investigation of both new and existing classes of natural products has once again become an important focus. In this review, we highlight how a medicinal chemistry/semi-synthetic approach to natural product manipulation continues to offer a valuable strategy to overcome limitations in current therapy. Approaches to address toxicity and to improve the solubility, bioavailability and the spectrum of activity are demonstrated. Examples are drawn from aminoglycosides, glycopeptides, tetracyclines, macrolides, thiazolyl peptides, pleuromutilins and polymyxins and are taken from the current literature, patents and abstracts of symposia. In many cases, this approach has led to drug candidates currently in late stages of clinical development., (© 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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218. Synthesis of mycothiol conjugate analogues and evaluation of their antimycobacterial activity.
- Author
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Riordan SW, Field JJ, Corkran HM, Dasyam N, Stocker BL, Timmer MS, Harvey JE, and Teesdale-Spittle PH
- Subjects
- Antitubercular Agents chemical synthesis, Cysteine chemical synthesis, Glycopeptides chemical synthesis, Inositol chemical synthesis, Microbial Sensitivity Tests, Mycobacterium tuberculosis drug effects, Antitubercular Agents chemistry, Antitubercular Agents pharmacology, Cysteine chemistry, Cysteine pharmacology, Glycopeptides chemistry, Glycopeptides pharmacology, Inositol chemistry, Inositol pharmacology
- Abstract
Drug-resistant Mycobacterium tuberculosis is a growing health problem. As proof of principle that the bacterial-specific metabolite mycothiol could be used as a delivery agent for antimycobacterial agents, simplified analogues of mycothiol were synthesised containing an S-trichloroethenyl substituted cysteine residue. It was envisaged that uptake of the mycothiol analogue would be followed by release of the known cytotoxin S-trichloroethenyl cysteine by the action of mycothiol S-conjugate amidase or its paralog, mycothiol deacetylase MshB. Promising activity was displayed against model Mycobacteria, although further development will be required to improve selectivity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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219. Structural changes in the thymus in allogenic pregnancy in mice with high incidence of spontaneous and muramylpeptide-induced abortions.
- Author
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Artem'eva KA, Boltovskaya MN, and Kalyuzhin OV
- Subjects
- Abortion, Spontaneous chemically induced, Animals, Body Weights and Measures, Crosses, Genetic, Female, Histological Techniques, Male, Mice, Mice, Inbred BALB C, Mice, Inbred CBA, Pregnancy, Statistics, Nonparametric, Thymus Gland drug effects, Abortion, Spontaneous pathology, Glycopeptides pharmacology, Thymus Gland pathology
- Abstract
Structural changes in the thymus over the course of allogenic pregnancy were studied in mice from highly fertile couples (CBA females and BALB/c males), animals with high spontaneous abortions (CBA females and DBA/2 males), and in experimental immunity-dependent pregnancy loss induced by muramyldipeptide β-heptylglycoside. Accidental involution of the thymus on days 8 and 14 of pregnancy was more pronounced in mice with high level of spontaneous embryo resorption than in females from highly fertile couples. Muramyldipeptide glycoside stimulated manifestations of thymus involution in fertile and "abortogenic" cross-breeding.
- Published
- 2014
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220. In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013.
- Author
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Karlowsky JA, Walkty AJ, Baxter MR, Adam HJ, and Zhanel GG
- Subjects
- Canada, Drug Resistance, Bacterial drug effects, Enterococcus faecalis drug effects, Glycopeptides administration & dosage, Gram-Positive Bacteria isolation & purification, Humans, Laboratories, Hospital, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Gram-Positive Bacteria drug effects, Gram-Positive Bacterial Infections microbiology
- Abstract
Gram-positive pathogens isolated in 15 Canadian hospital laboratories between 2011 and 2013 were tested for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute broth microdilution method. Oritavancin demonstrated in vitro activity equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against the isolates of methicillin-susceptible Staphylococcus aureus (n=1460; oritavancin MIC90, 0.06 μg/mL; 99.7% oritavancin-susceptible), methicillin-resistant S. aureus (n=427; oritavancin MIC90, 0.06 μg/mL; 99.5% oritavancin-susceptible), Streptococcus pyogenes (n=132; oritavancin MIC90, 0.25 μg/mL; 99.2% oritavancin-susceptible), Streptococcus agalactiae (n=156; oritavancin MIC90, 0.12 μg/mL; 100% oritavancin-susceptible), and Enterococcus faecalis (n=304; oritavancin MIC90, 0.06 μg/mL; 98.7% oritavancin-susceptible) tested., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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221. Three new agents added to the arsenal to fight MRSA.
- Author
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Strain J
- Subjects
- Anti-Bacterial Agents adverse effects, Anti-Bacterial Agents pharmacology, Drug Approval, Glycopeptides adverse effects, Glycopeptides pharmacology, Glycopeptides therapeutic use, Humans, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus isolation & purification, Organophosphates adverse effects, Organophosphates pharmacology, Organophosphates therapeutic use, Oxazoles adverse effects, Oxazoles pharmacology, Oxazoles therapeutic use, Streptococcal Infections microbiology, Teicoplanin adverse effects, Teicoplanin analogs & derivatives, Teicoplanin pharmacology, Teicoplanin therapeutic use, United States, United States Food and Drug Administration, Anti-Bacterial Agents therapeutic use, Methicillin-Resistant Staphylococcus aureus drug effects, Streptococcal Infections drug therapy
- Published
- 2014
222. Small molecule annotation for the Protein Data Bank.
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Sen S, Young J, Berrisford JM, Chen M, Conroy MJ, Dutta S, Di Costanzo L, Gao G, Ghosh S, Hudson BP, Igarashi R, Kengaku Y, Liang Y, Peisach E, Persikova I, Mukhopadhyay A, Narayanan BC, Sahni G, Sato J, Sekharan M, Shao C, Tan L, and Zhuravleva MA
- Subjects
- Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Binding Sites, Data Mining, Glucose chemistry, Glycopeptides chemistry, Glycopeptides pharmacology, Ligands, Models, Molecular, Reproducibility of Results, Small Molecule Libraries pharmacology, Databases, Chemical, Databases, Protein, Small Molecule Libraries chemistry
- Abstract
The Protein Data Bank (PDB) is the single global repository for three-dimensional structures of biological macromolecules and their complexes, and its more than 100,000 structures contain more than 20,000 distinct ligands or small molecules bound to proteins and nucleic acids. Information about these small molecules and their interactions with proteins and nucleic acids is crucial for our understanding of biochemical processes and vital for structure-based drug design. Small molecules present in a deposited structure may be attached to a polymer or may occur as a separate, non-covalently linked ligand. During curation of a newly deposited structure by wwPDB annotation staff, each molecule is cross-referenced to the PDB Chemical Component Dictionary (CCD). If the molecule is new to the PDB, a dictionary description is created for it. The information about all small molecule components found in the PDB is distributed via the ftp archive as an external reference file. Small molecule annotation in the PDB also includes information about ligand-binding sites and about covalent and other linkages between ligands and macromolecules. During the remediation of the peptide-like antibiotics and inhibitors present in the PDB archive in 2011, it became clear that additional annotation was required for consistent representation of these molecules, which are quite often composed of several sequential subcomponents including modified amino acids and other chemical groups. The connectivity information of the modified amino acids is necessary for correct representation of these biologically interesting molecules. The combined information is made available via a new resource called the Biologically Interesting molecules Reference Dictionary, which is complementary to the CCD and is now routinely used for annotation of peptide-like antibiotics and inhibitors., (© The Author(s) 2014. Published by Oxford University Press.)
- Published
- 2014
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223. In vivo enzyme inhibition improves the targeting of [177Lu]DOTA-GRP(13-27) in GRPR-positive tumors in mice.
- Author
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Marsouvanidis PJ, Melis M, de Blois E, Breeman WA, Krenning EP, Maina T, Nock BA, and de Jong M
- Subjects
- Animals, Cell Line, Tumor, Gastrin-Releasing Peptide pharmacokinetics, Heterografts, Humans, Lutetium chemistry, Male, Mice, Mice, Nude, Neprilysin metabolism, Peptide Fragments pharmacokinetics, Prostatic Neoplasms enzymology, Protease Inhibitors pharmacology, Radioisotopes chemistry, Radionuclide Imaging, Receptors, Bombesin metabolism, Tissue Distribution, Glycopeptides pharmacology, Neprilysin antagonists & inhibitors, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms metabolism, Radiopharmaceuticals pharmacokinetics, Receptors, Bombesin biosynthesis
- Abstract
Introduction: Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due to high receptor expression in frequently occurring human neoplasia. The authors recently synthesized a series of GRPR-affine peptide analogs based on the 27-mer GRP and derivatized with the DOTA chelator at the N-terminus for (111)In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with (177)Lu for future therapeutic applications. In addition, to improve in vivo stability of the peptide against in vivo degradation by the protease neutral endopeptidase (NEP), the authors coinjected [(177)Lu]DOTA-GRP(13-27) with the potent NEP inhibitor phosphoramidon (PA). The authors also aimed at reducing renal uptake by coadministration of lysine., Methods: In vivo stability studies were performed in Swiss albino mice. Biodistribution studies were conducted in NMRI nu/nu mice bearing prostate cancer (PC)-3 xenografts. Ex vivo autoradiography was performed using frozen sections from PC-3 xenografts and kidneys., Results and Discussion: Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [(177)Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios.
- Published
- 2014
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224. Antistaphylococcal activity of oritavancin and its synergistic effect in combination with other antimicrobial agents.
- Author
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Lin G, Pankuch G, Appelbaum PC, and Kosowska-Shick K
- Subjects
- Drug Synergism, Lipoglycopeptides, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects
- Abstract
Oritavancin exhibited in vitro activity against 169 strains of vancomycin-susceptible, methicillin-resistant Staphylococcus aureus (MRSA) with MICs ranging from 0.03 to 1 μg/ml and against vancomycin-intermediate MRSA (VISA; n = 29), heterogeneous vancomycin-intermediate MRSA (hVISA; n = 5), and vancomycin-resistant MRSA (n = 5) strains, with MICs ranging from 0.12 to 4 μg/ml. For 10 MRSA isolates comprising 5 VISA and 5 hVISA strains, synergy between oritavancin and gentamicin, linezolid, or rifampin was observed against most of the strains tested using a time-kill method., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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225. Potentiation of [Met5]enkephalin-induced antinociception by mixture of three peptidase inhibitors in rat.
- Author
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Murata T, Yoshikawa M, Watanabe M, Takahashi S, Kawaguchi M, Kobayashi H, and Suzuki T
- Subjects
- Analgesics administration & dosage, Animals, Captopril administration & dosage, Captopril pharmacology, Drug Synergism, Enkephalin, Methionine administration & dosage, Glycopeptides administration & dosage, Glycopeptides pharmacology, Male, Peptides administration & dosage, Peptides pharmacology, Protease Inhibitors administration & dosage, Rats, Rats, Wistar, Analgesics pharmacology, Enkephalin, Methionine pharmacology, Narcotic Antagonists pharmacology, Protease Inhibitors pharmacology
- Abstract
Purpose: Previous in vitro studies have shown that degradation of opioid peptides during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), namely, amastatin, captopril, and phosphoramidon. In the present in vivo study, we evaluate the effects of intrathecal administration of these PIs on antinociception by [Met(5)]enkephalin (ME) or PIs themselves., Methods: Drugs were administered into the thoracolumbar level of the spinal cord in the intrathecal space in rat. Induction of antinociception was measured by the tail immersion assay, with 55 °C as the nociceptive stimulus. Effects of PIs on antinociception were evaluated by dose-response study (ME, 1-20 nmol; PIs, 1-20 nmol each), by comparison of differences among two combinations of PIs (amastatin and captopril; captopril and phosphoramidon; amastatin and phosphoramidon) and three PIs (amastatin, captopril, and phosphoramidon), and by using opioid receptor selective antagonists., Results: Intrathecal administration of ME with these three PIs or PIs alone significantly and dose dependently increased antinociception in a μ- and δ-opioid receptor antagonist-reversible manner; moreover, the degree of antinociception with a combination of any two of these was less than that with all three, indicating that any residual single peptidase could inactivate significant amounts of ME., Conclusion: The present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in inactivation of opioid peptides at the spinal level.
- Published
- 2014
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226. The activity of glycopeptide antibiotics against resistant bacteria correlates with their ability to induce the resistance system.
- Author
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Kwun MJ and Hong HJ
- Subjects
- Drug Resistance, Bacterial, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Streptomyces coelicolor drug effects
- Abstract
Glycopeptide antibiotics containing a hydrophobic substituent display the best activity against vancomycin-resistant enterococci, and they have been assumed to be poor inducers of the resistance system. Using a panel of 26 glycopeptide derivatives and the model resistance system in Streptomyces coelicolor, we confirmed this hypothesis at the level of transcription. Identification of the structural glycopeptide features associated with inducing the expression of resistance genes has important implications in the search for more effective antibiotic structures., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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227. Noctilisin, a Venom Glycopeptide of Sirex noctilio (Hymenoptera: Siricidae), Causes Needle Wilt and Defense Gene Responses in Pines.
- Author
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Bordeaux JM, Lorenz WW, Johnson D, Badgett MJ, Glushka J, Orlando R, and Dean JF
- Subjects
- Amino Acid Sequence, Animals, Arthropod Venoms genetics, Base Sequence, Female, Glycopeptides genetics, Hymenoptera genetics, Insect Proteins genetics, Pinus genetics, Pinus immunology, Plant Leaves immunology, Plant Leaves physiology, Arthropod Venoms pharmacology, Glycopeptides pharmacology, Hymenoptera physiology, Insect Proteins pharmacology, Pinus physiology
- Abstract
During oviposition, female Sirex noctilio (F.) (Siricidae) woodwasps inject their conifer hosts with a venom gland secretion. The secretion induces a variety of host physiological changes that facilitate subsequent lethal infection by a symbiotic fungus. A heat-stable factor that can migrate from the site of oviposition in the trunk through the xylem to needles in the crown of attacked pines was purified by size-fractionation and reversed-phase-high-performance liquid chromatography using activity assays based on defense gene induction as well as the needle wilt response in pine shoot explants. An 11-amino acid, posttranslationally modified peptide (SEGPROGTKRP) encoded by the most abundant transcript recovered from S. noctilio venom gland tissue comprised the backbone of the 1,850 Da active factor. Posttranslational modifications included hydroxylation of a Pro residue at position 6 as well as O-glycosylation of Ser and Thr residues at positions 1 and 8, respectively. The O-linked sugars were identical α-linked N-acetylgalactosamine residues modified at the C6 position by addition of phosphoethanolamine. In contrast to the native peptide, a synthetic version of the hydroxylated peptide backbone lacking the glycosyl side chains failed to induce pine defense genes or cause needle wilt in excised shoots. This peptide, hereafter called noctilisin, is related to the O-glycosylated short-chain proline-rich antimicrobial peptides exemplified by drosocin. The noctilisin structure contains motifs which may explain how it avoids detection by pine defense systems., (© 2014 Entomological Society of America.)
- Published
- 2014
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228. Oritavancin: first global approval.
- Author
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Markham A
- Subjects
- Anti-Bacterial Agents chemistry, Glycopeptides chemistry, Humans, Lipoglycopeptides, Microbial Sensitivity Tests, Skin Diseases, Bacterial microbiology, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Approval, Glycopeptides pharmacology, Glycopeptides therapeutic use, Gram-Positive Bacteria drug effects, Skin Diseases, Bacterial drug therapy
- Abstract
Oritavancin (Orbactiv(®)) is a lipoglycopeptide antibacterial drug with activity against Gram-positive bacteria developed by The Medicines Company as a single-dose treatment for acute bacterial skin and skin structure infections (ABSSSI). The drug received its first global approval for this indication in the US in August 2014, and is under regulatory review in the EU. This article summarises the milestones in the development of oritavancin leading to this first approval for the treatment of ABSSSIs caused by Gram-positive bacteria.
- Published
- 2014
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229. Glycopeptide antibiotics: back to the future.
- Author
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Butler MS, Hansford KA, Blaskovich MA, Halai R, and Cooper MA
- Subjects
- Animals, Anti-Bacterial Agents pharmacokinetics, Drug Approval, Drug Design, Drug Resistance, Bacterial, Glycopeptides pharmacokinetics, Gram-Negative Bacteria drug effects, Gram-Positive Bacterial Infections microbiology, Humans, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Gram-Positive Bacterial Infections drug therapy
- Abstract
Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin (2), still used extensively. The increased occurrence of resistance and the effectiveness of these 'last resort' treatments for Gram-positive infections has led to the discovery and clinical development of second generation, semisynthetic lipoglycopeptide derivatives such as telavancin (3), dalbavancin (4) and oritavancin (5), which all possess broader spectra of activity and improved pharmacokinetic properties. Two of these new antibiotics, telavancin (3) and dalbavancin (4), were approved in the past 5 years and the third, oritavancin (5), is awaiting regulatory approval. In this review, the discovery, development and associated resistance of vancomycin (1) and teicoplanin (2), and semi-synthetic glycopeptides, telavancin (3), dalbavancin (4) and oritavancin (5), are detailed. The clinical implications of glycopeptide resistance, especially vancomycin (1), as well as the future prospects for current glycopeptide drugs and the development of new glycopeptides are discussed.
- Published
- 2014
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230. Experimental study of the efficacy of linezolid alone and in combinations against experimental meningitis due to Staphylococcus aureus strains with decreased susceptibility to beta-lactams and glycopeptides.
- Author
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Cabellos C, Garrigós C, Taberner F, Force E, and Pachón-Ibañez ME
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Disease Models, Animal, Drug Resistance, Multiple, Bacterial, Drug Therapy, Combination methods, Female, Linezolid, Meningitis, Bacterial microbiology, Microbial Sensitivity Tests, Rabbits, Random Allocation, Rifampin pharmacology, Vancomycin pharmacology, beta-Lactam Resistance, Acetamides pharmacology, Glycopeptides pharmacology, Meningitis, Bacterial drug therapy, Oxazolidinones pharmacology, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Staphylococcus aureus drug effects, beta-Lactams pharmacology
- Abstract
Background: To evaluate in vitro and in vivo efficacies of linezolid, vancomycin, and the combination of linezolid and rifampicin against two Staphylococcus aureus strains with reduced susceptibility to beta-lactams and one of them also to glycopeptides., Methods: In vitro killing curves and a rabbit model: Meningitis was induced by intracisternal inoculation of 10(8) CFU/ml of each strain. Five hours later (0 h), rabbits were randomly assigned to control or to therapeutic groups. CSF bacterial counts, lactate and protein concentrations, and pharmacokinetic parameters were determined., Results: In vivo: linezolid and its combination with rifampicin reduced bacterial concentrations at 24 h, median cfu/mL 4.85 vs 3.87 (p < 0.05) for linezolid and 5.02 vs 4.21 (p < 0.05) for linezolid + rifampicin, against the glycopeptide intermediate S. aureus (GISA) strain and improved inflammatory parameters., Conclusions: Despite the need for more experimental data, our results suggest that linezolid and its combinations could be considered as a potential alternative in difficult-to-treat CNS infections and especially in those due to GISA strains and deserve more studies., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2014
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231. Total synthesis and stereochemistry revision of mannopeptimycin aglycone.
- Author
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Fuse S, Koinuma H, Kimbara A, Izumikawa M, Mifune Y, He H, Shin-ya K, Takahashi T, and Doi T
- Subjects
- Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Cyclization, Glycopeptides chemistry, Glycopeptides pharmacology, Magnetic Resonance Spectroscopy, Molecular Structure, Staphylococcus aureus drug effects, Stereoisomerism, Structure-Activity Relationship, Anti-Bacterial Agents chemical synthesis, Glycopeptides chemical synthesis
- Abstract
Development of efficient methods for preparation of bioactive nonribosomal peptides, containing densely functionalized nonproteinogenic amino acids, is an important task in organic synthesis. We have employed a concise synthesis for such amino acids by asymmetric aldol addition coupled with an isomeric resolution via diastereoselective cyclization. This approach is successfully applied to the first total synthesis of the cyclic hexapeptide aglycone of the mannopeptimycins, a group of glycopeptides known for potent activity against drug-resistant bacteria. The facile preparation of the key amino acids and the synthesis of the aglycone pave the way for further studies on this class of antibiotics and the development of new lead compounds with therapeutic potential. In addition, our studies have led to the revision of the stereochemistry of the β-methylphenylalanine residue in the mannopeptimycin aglycone.
- Published
- 2014
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232. Multiple complexes of long aliphatic N-acyltransferases lead to synthesis of 2,6-diacylated/2-acyl-substituted glycopeptide antibiotics, effectively killing vancomycin-resistant enterococcus.
- Author
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Lyu SY, Liu YC, Chang CY, Huang CJ, Chiu YH, Huang CM, Hsu NS, Lin KH, Wu CJ, Tsai MD, and Li TL
- Subjects
- Acylation, Acyltransferases chemistry, Anti-Bacterial Agents chemistry, Biocatalysis, Chemistry Techniques, Synthetic, Glycopeptides chemistry, Models, Molecular, Protein Structure, Tertiary, Structure-Activity Relationship, Acyltransferases metabolism, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents pharmacology, Glycopeptides chemical synthesis, Glycopeptides pharmacology, Vancomycin-Resistant Enterococci drug effects
- Abstract
Teicoplanin A2-2 (Tei)/A40926 is the last-line antibiotic to treat multidrug-resistant Gram-positive bacterial infections, e.g., methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). This class of antibiotics is powered by the N-acyltransferase (NAT) Orf11*/Dbv8 through N-acylation on glucosamine at the central residue of Tei/A40926 pseudoaglycone. The NAT enzyme possesses enormous value in untapped applications; its advanced development is hampered largely due to a lack of structural information. In this report, we present eight high-resolution X-ray crystallographic unary, binary, and ternary complexes in order to decipher the molecular basis for NAT's functionality. The enzyme undergoes a multistage conformational change upon binding of acyl-CoA, thus allowing the uploading of Tei pseudoaglycone to enable the acyl-transfer reaction to take place in the occlusion between the N- and C-halves of the protein. The acyl moiety of acyl-CoA can be bulky or lengthy, allowing a large extent of diversity in new derivatives that can be formed upon its transfer. Vancomycin/synthetic acyl-N-acetyl cysteamine was not expected to be able to serve as a surrogate for an acyl acceptor/donor, respectively. Most strikingly, NAT can catalyze formation of 2-N,6-O-diacylated or C6→C2 acyl-substituted Tei analogues through an unusual 1,4-migration mechanism under stoichiometric/solvational reaction control, wherein selected representatives showed excellent biological activities, effectively counteracting major types (VanABC) of VRE.
- Published
- 2014
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233. Is prediffusion test an alternative to improve accuracy in screening hVISA strains and to detect susceptibility to glycopeptides/lipopeptides?
- Author
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Silveira AC, Sambrano GE, Paim TG, Caierão J, Cordova CM, and d'Azevedo PA
- Subjects
- Disk Diffusion Antimicrobial Tests, Humans, Reproducibility of Results, Staphylococcal Infections diagnosis, Staphylococcus aureus isolation & purification, Glycopeptides pharmacology, Lipopeptides pharmacology, Microbial Sensitivity Tests methods, Staphylococcal Infections microbiology, Staphylococcus aureus drug effects, Vancomycin Resistance
- Abstract
The characterization of heteroresistant vancomycin-intermediate Staphylococcus aureus strains (hVISA) is even more challenging, as no routine standardized laboratory methods are available. A total of 124 S. aureus isolates recovered from inpatients attended in hospitals of Santa Catarina State, Southern Brazil, were evaluated. The MIC of vancomycin, teicoplanin, and daptomycin was determined by Etest and prediffusion tests using NeoSensitabs® tablets. All isolates were susceptible to vancomycin (MICs: 0.5-3 μg/mL) by Etest. However, according to prediffusion test, 17 isolates presented reduced susceptibility to vancomycin, and of these, 12 were confirmed as hVISA using populational analysis. Considering daptomycin, prediffusion results were in agreement with susceptibility data (MICs), as all isolates were susceptible. Considering that characterizing hVISA is challenging and that MIC determination is not adequate to characterize this phenotype, prediffusion test was a viable alternative to screening hVISA and reduced susceptibility to vancomycin. It was simple and low cost, with accuracy comparable to other well-established methods., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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234. In vitro activities of oritavancin and comparators against meticillin-resistant Staphylococcus aureus (MRSA) isolates harbouring the novel mecC gene.
- Author
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Arhin FF, Sarmiento I, and Moeck G
- Subjects
- Acetamides pharmacology, Daptomycin pharmacology, Gene Expression, Linezolid, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus genetics, Methicillin-Resistant Staphylococcus aureus growth & development, Methicillin-Resistant Staphylococcus aureus isolation & purification, Microbial Sensitivity Tests, Microbial Viability drug effects, Oxazolidinones pharmacology, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Bacterial Proteins genetics, Glycopeptides pharmacology, Methicillin Resistance genetics, Methicillin-Resistant Staphylococcus aureus drug effects
- Abstract
Meticillin-resistant Staphylococcus aureus (MRSA) is routinely detected by amplification of the mecA gene. Recently, MRSA isolates harbouring a novel mec gene (mecC) that is not detected by mecA amplification have been reported. In this study, the activities of the lipoglycopeptide oritavancin as well as the comparators vancomycin, daptomycin and linezolid against 14 mecC MRSA isolates were studied by broth microdilution minimum inhibitory concentration (MIC) and time-kill assays at clinically relevant concentrations of each antibacterial agent. Oritavancin, vancomycin, daptomycin and linezolid MIC90 values (MIC required to inhibit 90% of the isolates) against the mecC isolates were 0.06, 1, 1 and 2mg/L, respectively. In time-kill assays, oritavancin at concentrations reflective of its free peak in plasma of patients receiving a single 1200 mg intravenous dose and the level 24h thereafter was bactericidal against all isolates tested, attaining 3 log kill relative to the starting inoculum between 5 min and 15 min. Vancomycin both at its free peak and free trough concentrations was also bactericidal against all isolates, attaining bactericidal activity between 6h and 24h. Daptomycin was bactericidal only at its free peak concentration, attaining bactericidal activity between 30 min and 4h against the tested isolates. Linezolid was bacteriostatic (<3 log kill relative to the starting inoculum) against the tested isolates. Oritavancin's in vitro activity against mecC MRSA isolates was indistinguishable from that against mecA MRSA isolates both in MIC and time-kill assays., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)
- Published
- 2014
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- View/download PDF
235. Emerging bioinspired polymers: glycopolypeptides.
- Author
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Krannig KS and Schlaad H
- Subjects
- Glycopeptides chemistry, Glycopeptides pharmacology, Glycosylation, Lectins metabolism, Protein Binding, Glycopeptides chemical synthesis, Polymerization
- Abstract
This article highlights the very recent advances in glycopolypeptide synthesis via NCA polymerization and first studies on stimuli-responsive solution behavior and self-assembling structures. Yet glycopolypeptides are almost exclusively considered as smart biofunctional materials for use in biomedical applications, for instance in targeted drug delivery, but also have high potential for usage as structural materials to fabricate bioinspired hierarchical structures.
- Published
- 2014
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236. Heterogeneous glycopeptide intermediate Staphylococcus epidermidis isolated from prosthetic joint infections.
- Author
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Tevell S, Claesson C, Hellmark B, Söderquist B, and Nilsdotter-Augustinsson Å
- Subjects
- Humans, Microbial Sensitivity Tests, Staphylococcus epidermidis isolation & purification, Sweden, Teicoplanin pharmacology, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial, Glycopeptides pharmacology, Joints microbiology, Prosthesis-Related Infections microbiology, Staphylococcal Infections microbiology, Staphylococcus epidermidis drug effects
- Abstract
Methicillin-resistant Staphylococcus epidermidis (MRSE) poses a major problem in prosthetic joint infections (PJIs). Vancomycin is often considered the drug of choice in the empirical treatment of staphylococcal PJIs. As recent decades have seen reports of heterogeneous glycopeptide intermediate S. aureus (hGISA), our aim was to examine the prevalence of heterogeneous glycopeptide intermediate S. epidermidis (hGISE) in PJIs. S. epidermidis isolates (n = 122) from 119 patients in three Swedish counties between 1993 and 2012 were included. All were isolated from perioperative tissue samples from revision surgery in clinically verified PJIs. Antimicrobial susceptibility testing against staphylococcal antibiotics was performed. The macromethod Etest (MME) and glycopeptide resistance detection (GRD) Etest were used to detect hGISE. Standard minimal inhibitory concentration (MIC) determination revealed no vancomycin-resistant isolates, while teicoplanin resistance was detected in 14 out of 122 isolates (11.5%). hGISE was found in 95 out of 122 isolates (77.9%), 64 out of 67 of isolates with teicoplanin MIC >2 mg/L (95.5%) and 31 out of 55 of isolates with teicoplanin MIC ≤2 mg/L (56.4%). Thus, the presence of hGISE cannot be ruled out by teicoplanin MIC ≤2 mg/L alone. Multidrug resistance was detected in 86 out of 95 hGISE isolates (90.5%) and in 16 out of 27 isolates (59.3%), where hGISE could not be detected. In conclusion, hGISE detected by MME or GRD was common in this material. However, hGISE is difficult to detect with standard laboratory diagnostic routines. Glycopeptide treatment may not be sufficient in many of these PJIs, even if standard MIC classifies the isolated S. epidermidis as susceptible.
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- 2014
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237. Activity of oritavancin tested against uncommonly isolated Gram-positive pathogens responsible for documented infections in hospitals worldwide.
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Mendes RE, Sader HS, Flamm RK, and Jones RN
- Subjects
- Anti-Bacterial Agents pharmacology, Cross Infection epidemiology, Global Health, Gram-Positive Bacteria isolation & purification, Gram-Positive Bacterial Infections epidemiology, Hospitals, Humans, Inhibitory Concentration 50, Lipoglycopeptides, Microbial Sensitivity Tests, Staphylococcus drug effects, Staphylococcus isolation & purification, Streptococcus drug effects, Streptococcus isolation & purification, Cross Infection microbiology, Glycopeptides pharmacology, Gram-Positive Bacteria drug effects, Gram-Positive Bacterial Infections microbiology
- Abstract
Objectives: To assess the oritavancin spectrum and activity against 2811 rarer species of coagulase-negative staphylococci (CoNS), streptococci and other Gram-positive species., Methods: A total of 2057 CoNS (14 species), 674 streptococci (7 groups) and 80 other Gram-positive species (3 genera) collected over a 5 year period as part of the SENTRY Program (2008-12) were included. Isolates were primarily identified by the participating laboratory and identification was confirmed by the reference monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A9 and M100-S23 documents., Results: Overall, oritavancin was active against all CoNS (MIC50/MIC90, 0.015/0.06 mg/L), with MIC50 values of ≤0.008-0.03 mg/L. Streptococci exhibited oritavancin MIC50 results of ≤0.008 mg/L, except for the Streptococcus bovis (0.03 mg/L), Streptococcus dysgalactiae (0.06 mg/L) and Streptococcus salivarius/vestibularis (0.06 mg/L) groups. Micrococcus spp., Listeria monocytogenes and Corynebacterium spp. had oritavancin MIC50 results of ≤0.008 mg/L., Conclusions: This study expands the oritavancin in vitro data against several species of Gram-positive organisms., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
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- 2014
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238. Molecular modeling of Gram-positive bacteria peptidoglycan layer, selected glycopeptide antibiotics and vancomycin derivatives modified with sugar moieties.
- Author
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Ślusarz R, Szulc M, and Madaj J
- Subjects
- Amino Acid Sequence, Aminoglycosides chemistry, Aminoglycosides metabolism, Aminoglycosides pharmacology, Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Carbohydrate Conformation, Glycopeptides chemistry, Glycopeptides metabolism, Glycopeptides pharmacology, Lipoglycopeptides, Peptidoglycan metabolism, Vancomycin metabolism, Vancomycin pharmacology, Anti-Bacterial Agents chemistry, Bacillus subtilis drug effects, Molecular Dynamics Simulation, Peptidoglycan chemistry, Staphylococcus aureus drug effects, Vancomycin chemistry
- Abstract
Proper understanding of the mechanisms of binding to Gram-positive bacteria cell wall layers-especially to the peptidoglycan (PG) layer, seems to be crucial for proper development of new drug candidates which are effective against these bacteria. In this work we have constructed two different models of the Gram-positive bacteria PG layer: the layered and the scaffold models. PG conformational changes during geometry optimization, models relaxation, and molecular dynamics were described and discussed. We have found that the border surface of both PG layer models differs from the surface located away from the edge of models and the chains formed by disaccharide units prefer helix-like conformation. This curling of PG chains significantly affects the shape of antibiotic-accessible surface and the process is thus crucial for new drug development. Glycopeptide antibiotics effective against Gram-positive bacteria, such as vancomycin and its semisynthetic derivatives-oritavancin and telavancin, bind to d-alanyl-d-alanine stem termini on the peptidoglycan precursors of the cell wall. This binding inhibits cross-linking between the peptides and subsequently prevents cell wall synthesis. In this study some of the aspects of conformational freedom of vancomycin and restrictions from the modifications of vancomycin structure introduced into oritavancin and telavancin and five other vancomycin derivatives (with addition of 2-acetamido-2-deoxy-β-d-galactopyranosylamine, 2-acetamido-2-deoxy-β-d-glucopyranosylamine, 1-amine-1-deoxy-d-glucitol, 2-amino-2-deoxy-d-galactitol, or 2-amino-2-deoxy-d-glucitol to the C-terminal amino acid group in the vancomycin) are presented and discussed. The resulting molecular dynamics trajectories, root mean square deviation changes of aglycon and saccharide moieties as well as a comparative study of possible interactions with cyclic and chain forms of modified groups have been carried out, measured, and analyzed. Energetically advantageous conformations show close similarity to the structures known from the experimental data, but the diversity of others suggest very high conformational freedom of all modeled antibiotics and vancomycin derivatives. Alditol derivatives move closer to the peptidoglycan chain more easily but they also form intramolecular interactions more frequently than their homologous cyclic forms. One of the proposed derivatives seems to be a promising agent which is efficient in treatment of infections caused by Gram-positive bacteria., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
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- 2014
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239. Oritavancin activity against Staphylococcus aureus causing invasive infections in U.S. and European hospitals: a 5-year international surveillance program.
- Author
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Mendes RE, Sader HS, Flamm RK, Farrell DJ, and Jones RN
- Subjects
- Drug Resistance, Multiple, Bacterial, Europe, Hospitals, Lipoglycopeptides, Microbial Sensitivity Tests, United States, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Staphylococcus aureus drug effects
- Abstract
In this study, oritavancin had modal MIC, MIC50, and MIC90 values of 0.03, 0.03, and 0.06 μg/ml, respectively, against Staphylococcus aureus. Similar results (MIC50/90, 0.03/0.06 μg/ml) were observed against methicillin-resistant and -susceptible isolates and those demonstrating multidrug-resistant (MDR) and non-MDR phenotypes. When oritavancin (MIC50/90, 0.06/0.12 mg/ml) was tested against S. aureus with elevated MIC values for daptomycin (i.e., 1 to 4 mg/ml) and vancomycin (i.e., 2 mg/ml), it showed MIC results 2-fold higher than those for the more susceptible vancomycin or daptomycin counterparts (MIC50/90, 0.03/0.06 mg/ml), yet it inhibited these isolates at ≤0.25 mg/ml.
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- 2014
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240. Hydroxyproline substitutions stabilize non-glycosylated drosocin against serum proteases without challenging its antibacterial activity.
- Author
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Knappe D, Cassone M, Nollmann FI, Otvos L, and Hoffmann R
- Subjects
- Amino Acid Sequence, Animals, Anti-Bacterial Agents blood, Anti-Bacterial Agents pharmacology, Cell Line, Drug Stability, Escherichia coli drug effects, Escherichia coli Infections drug therapy, Glycopeptides blood, Glycopeptides pharmacology, Glycosylation, Half-Life, Humans, Klebsiella Infections drug therapy, Klebsiella pneumoniae drug effects, Mice, Microbial Sensitivity Tests, Molecular Sequence Data, Peptide Hydrolases blood, Peptides blood, Peptides chemistry, Peptides metabolism, Peptides pharmacology, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents metabolism, Glycopeptides chemistry, Glycopeptides metabolism, Hydroxyproline chemistry, Peptide Hydrolases metabolism
- Abstract
The increasing incidence of multi- and pan-resistant pathogens demands novel compounds to fight Grampositive and especially Gram-negative bacteria. Among the currently investigated compound classes, antimicrobial peptides (AMPs) inhibiting specific bacterial targets appear especially promising for systemic therapy of infections, although unmodified linear peptides are typically rapidly degraded by serum proteases. Proline-rich AMPs have been heavily investigated in recent years due to their low toxicity and proven in vivo efficacy. Here, we report novel unglycosylated drosocin analogs with extended half-life in mouse serum and improved activity against Gram-negative pathogens Escherichia coli and Klebsiella pneumoniae. Substituting proline (Pro) residues in positions 3, 5, 10, and 14 with trans-4-hydroxy-Lproline ((t)Hyp) improved the antibacterial activity, whereas substitution of Pro-16 reduced the activity. Drosocin analogs with (t)Hyp in positions 3 and 5 were also four to eight times more stable in mouse serum than the unmodified analog. The new compounds were not toxic against human HeLa, HEK293, and HepG2 cell lines and showed no hemolytic activity against human erythrocytes at peptide concentrations of at least 600 µg/mL.
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- 2014
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241. Spinal ERK2 activation through δ2-opioid receptors contributes to nociceptive behavior induced by intrathecal injection of leucine-enkephalin.
- Author
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Komatsu T, Katsuyama S, Mizoguchi H, Sakurada C, Tsuzuki M, Sakurada S, and Sakurada T
- Subjects
- Animals, Arginine analogs & derivatives, Arginine pharmacology, Behavior, Animal drug effects, Butadienes pharmacology, Enkephalin, Leucine administration & dosage, Enzyme Activation drug effects, Glycopeptides pharmacology, Injections, Spinal, Leucine analogs & derivatives, Leucine pharmacology, Male, Mice, Inbred Strains, NG-Nitroarginine Methyl Ester pharmacology, Naltrexone analogs & derivatives, Naltrexone pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nitriles pharmacology, Protease Inhibitors pharmacology, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Receptors, Opioid, delta antagonists & inhibitors, Spinal Cord metabolism, Enkephalin, Leucine pharmacology, Mitogen-Activated Protein Kinase 1 metabolism, Nociception drug effects, Receptors, Opioid, delta metabolism, Spinal Cord drug effects
- Abstract
Intrathecal (i.t.) injection of leucine-enkephalin (Leu-ENK), co-administered with peptidase inhibitors, phosphoramidon (an endopeptidase 24.11 inhibitor), and bestatin (a general aminopeptidase inhibitor), produced behaviors consisting of the biting and/or licking of the hindpaw and the tail along with hindlimb scratching directed toward the flank, which peaked at 10-15 min after an injection. This characteristic behavior was not observed in mice treated with i.t. Leu-ENK alone. We also investigated the effect of the extracellular signal-regulated kinase (ERK) in spinal processing of nociception induced by i.t. co-administration of Leu-ENK with phospharamidon and bestatin. Western blot analysis of phospho-ERK (pERK) showed a significant increase of pERK2 in the lumbar spinal cord in response to i.t. Leu-ENK co-injected with peptidase inhibitors. The MAP kinase-ERK inhibitor, U0126 dose-dependently attenuated the nociceptive behavior and spinal ERK activation to i.t. Leu-ENK co-injected with peptidase inhibitors. Furthermore, the nociceptive behavior and spinal ERK activation evoked by i.t. Leu-ENK in combination with peptidase inhibitors were inhibited by co-administration of the non-selective δ-opioid receptor antagonist, naltrindole, the selective δ2-opioid receptor antagonist, naltriben, the non-competitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 or the non-selective nitric oxide synthase inhibitor, L-NAME, the selective nNOS inhibitor, N(ω)-propyl-L-arginine or the selective iNOS inhibitor, W1400, but not by the selective δ1-receptor antagonist, BNTX (7-benzylidenenaltrexone). These results suggest that spontaneous nociceptive behaviors produced by i.t. co-administration of Leu-ENK with peptidase inhibitors may be induced by an activation of the glutamate-NO-ERK pathway through the δ2-opioid receptor in the dorsal spinal cord., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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242. The rise and fall of mandatory surveillance for glycopeptide-resistant enterococcal bacteraemia in England.
- Author
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Gouliouris T and Peacock SJ
- Subjects
- Bacteremia microbiology, England epidemiology, Gram-Positive Bacterial Infections microbiology, Humans, Incidence, Bacteremia epidemiology, Drug Resistance, Bacterial, Enterococcus drug effects, Epidemiological Monitoring, Glycopeptides pharmacology, Gram-Positive Bacterial Infections epidemiology
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- 2014
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243. Antimicrobial glycopeptides: synthesis and antibacterial activity of N-linked and O-linked smaller chain glycopeptides.
- Author
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Nagarajan K, Taleuzzamman M, Kumar V, Singh S, Singh J, Panda BP, and Ghosh LK
- Subjects
- Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Gram-Negative Bacteria drug effects, Gram-Positive Bacteria drug effects, Microbial Sensitivity Tests, Anti-Bacterial Agents chemical synthesis, Glycopeptides chemical synthesis
- Abstract
Our objective is to synthesize the smaller chain N-linked and O-linked glycopeptides using sugars belong to mono, di and polysaccharides, with the efforts mainly directed towards the identification of antibacterial compounds. 7 glycopeptides, viz., Arg-Asn-Mannose, Arg-Asn-Lactose, His-Asn-Mannose, His-Asn-Lactose (N-glycopeptides), Arg-Ser-Lactose, Arg-Thr-Lactose, Arg-Thr-Starch (O-glycopeptides) were prepared by dicyclohexyl carbodimide (DCC) coupling for amino acids using microwave oven (50W power; 15 min) and activated and coupled with respective sugar moieties using microwave oven at 120 W for 20-25 min. The column eluted compounds were tested for disc diffusion assay using 3 gram positive S. aureus, B. subtilis, S. caprae and 3 gram negative E. coli, P. aeruginosa and S. sonnei strains at different concentrations predicted by pH and inhibitory concentrations. One of the test glycopeptide, His-Asn-Lactose was found to be very effective against all the microbial strains tested and 3 other Test Compounds, viz., His-Asn-Mannose, Arg-Thr-Lactose and Arg-Thr-Starch are also proved to be effective against 2 gram positive and 2 gram negative strains tested. Maximum activity was observed at a concentration of 450 μg/ml (747.51 µM) for the N-glycopeptide His-Asn-Lactose with the corresponding zonal inhibition diameters (15 mm; 19 mm; 14 mm; 18 mm; 16 mm; 17 mm) against S. aureus, B. subtilis, S. caprae, E. coli, P. aeruginosa, S. sonnei. This is the first evidence based report that our N-glycopeptide, His-Asn-Lactose tested, has shown antibacterial action against both gram positive and gram negative strains. Further in vivo testing and clinical studies will make sure to position our potent small chain N-glycopeptide in the arsenal of new broad spectrum anti-gram positive and negative agent., (© Georg Thieme Verlag KG Stuttgart · New York.)
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- 2014
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244. Theonellamide G, a potent antifungal and cytotoxic bicyclic glycopeptide from the Red Sea marine sponge Theonella swinhoei.
- Author
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Youssef DT, Shaala LA, Mohamed GA, Badr JM, Bamanie FH, and Ibrahim SR
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma pathology, Animals, Antifungal Agents chemistry, Antifungal Agents isolation & purification, Antineoplastic Agents chemistry, Antineoplastic Agents isolation & purification, Candida albicans drug effects, Chromatography, High Pressure Liquid, Colonic Neoplasms drug therapy, Colonic Neoplasms pathology, Glycopeptides chemistry, Glycopeptides isolation & purification, Glycopeptides pharmacology, HCT116 Cells, Humans, Indian Ocean, Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Peptides, Cyclic chemistry, Peptides, Cyclic isolation & purification, Peptides, Cyclic pharmacology, Antifungal Agents pharmacology, Antineoplastic Agents pharmacology, Theonella chemistry
- Abstract
In our search for bioactive metabolites from marine organisms, we have investigated the polar fraction of the organic extract of the Red Sea sponge Theonella swinhoei. Successive chromatographic separations and final HPLC purification of the potent antifungal fraction afforded a new bicyclic glycopeptide, theonellamide G. The structure of the peptide was determined using extensive 1D and 2D NMR and high-resolution mass spectral determinations. The absolute configuration of theonellamide G was determined by chemical degradation and 2D NMR spectroscopy. Theonellamide G showed potent antifungal activity towards wild and amphotericin B-resistant strains of Candida albicans with IC₅₀ of 4.49 and 2.0 μM, respectively. Additionally, it displayed cytotoxic activity against the human colon adenocarcinoma cell line (HCT-16) with IC₅₀ of 6.0 μM. These findings provide further insight into the chemical diversity and biological activities of this class of compounds.
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- 2014
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245. A small RNA controls a protein regulator involved in antibiotic resistance in Staphylococcus aureus.
- Author
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Eyraud A, Tattevin P, Chabelskaya S, and Felden B
- Subjects
- Anti-Bacterial Agents pharmacology, Bacterial Proteins genetics, Bacterial Proteins metabolism, Glycopeptides pharmacology, Operon, Peptide Chain Initiation, Translational, RNA, Bacterial chemistry, RNA, Messenger chemistry, RNA, Small Untranslated chemistry, Staphylococcus aureus metabolism, Drug Resistance, Bacterial genetics, RNA, Bacterial metabolism, RNA, Small Untranslated metabolism, Staphylococcus aureus drug effects, Staphylococcus aureus genetics
- Abstract
The emergence of Staphylococcus aureus strains that are resistant to glycopeptides has led to alarming scenarios where serious staphylococcal infections cannot be treated. The bacterium expresses many small regulatory RNAs (sRNAs) that have unknown biological functions for the most part. Here we show that an S. aureus sRNA, SprX (alias RsaOR), shapes bacterial resistance to glycopeptides, the invaluable treatments for Methicillin-resistant staphylococcal infections. Modifying SprX expression levels influences Vancomycin and Teicoplanin glycopeptide resistance. Comparative proteomic studies have identified that SprX specifically downregulates stage V sporulation protein G, SpoVG. SpoVG is produced from the yabJ-spoVG operon and contributes to S. aureus glycopeptide resistance. SprX negatively regulates SpoVG expression by direct antisense pairings at the internal translation initiation signals of the second operon gene, without modifying bicistronic mRNA expression levels or affecting YabJ translation. The SprX and yabJ-spoVG mRNA domains involved in the interaction have been identified, highlighting the importance of a CU-rich loop of SprX in the control of SpoVG expression. We have shown that SpoVG might not be the unique SprX target involved in the glycopeptide resistance and demonstrated that the regulation of glycopeptide sensitivity involves the CU-rich domain of SprX. Here we report the case of a sRNA influencing antibiotic resistance of a major human pathogen.
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- 2014
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246. Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to β-endorphin?
- Author
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Li Y, St Louis L, Knapp BI, Muthu D, Anglin B, Giuvelis D, Bidlack JM, Bilsky EJ, and Polt R
- Subjects
- Animals, CHO Cells, Circular Dichroism, Cricetinae, Cricetulus, Drug Design, Glycopeptides chemical synthesis, Humans, Injections, Intravenous, Injections, Intraventricular, Magnetic Resonance Spectroscopy, Male, Mice, Micelles, Models, Molecular, Protein Conformation, Protein Structure, Secondary, Receptors, Opioid, delta metabolism, Receptors, Opioid, kappa drug effects, Receptors, Opioid, mu metabolism, Structure-Activity Relationship, Analgesics chemical synthesis, Analgesics pharmacology, Glycopeptides chemistry, Glycopeptides pharmacology, beta-Endorphin analogs & derivatives, beta-Endorphin pharmacology
- Abstract
Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-, or κ-opioid receptors in the low nanomolar range (2.2-35 nM K(i)'s). The glycoside moiety was required for intravenous (i.v.) but not for intracerebroventricular (i.c.v.) activity. Circular dichroism and NMR indicated the degree of helicity in H2O, aqueous trifluoroethanol, or micelles. Glycosylation was essential for activity after i.v. administration. It was possible to manipulate the degree of helicity by the alteration of only two amino acid residues in the helical address region of the β-endorphin analogues without destroying μ-, δ-, or κ-agonism, but the antinociceptive activity after i.v. administration could not be directly correlated to the degree of helicity in micelles.
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- 2014
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247. Surface-stress sensors for rapid and ultrasensitive detection of active free drugs in human serum.
- Author
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Ndieyira JW, Kappeler N, Logan S, Cooper MA, Abell C, McKendry RA, and Aeppli G
- Subjects
- Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Bacteria drug effects, Bacteria metabolism, Biomechanical Phenomena, Biosensing Techniques instrumentation, Equipment Design, Glycopeptides metabolism, Glycopeptides pharmacology, Humans, Ligands, Lipoglycopeptides, Models, Biological, Solvents metabolism, Surface Properties, Vancomycin metabolism, Vancomycin pharmacology, Anti-Bacterial Agents blood, Glycopeptides blood, Nanotechnology instrumentation, Vancomycin blood
- Abstract
There is a growing appreciation that mechanical signals can be as important as chemical and electrical signals in biology. To include such signals in a systems biology description for understanding pathobiology and developing therapies, quantitative experiments on how solution-phase and surface chemistry together produce biologically relevant mechanical signals are needed. Because of the appearance of drug-resistant hospital 'superbugs', there is currently great interest in the destruction of bacteria by bound drug-target complexes that stress bacterial cell membranes. Here, we use nanomechanical cantilevers as surface-stress sensors, together with equilibrium theory, to describe quantitatively the mechanical response of a surface receptor to different antibiotics in the presence of competing ligands in solution. The antibiotics examined are the standard, Food and Drug Administration-approved drug of last resort, vancomycin, and the yet-to-be approved oritavancin, which shows promise for controlling vancomycin-resistant infections. The work reveals variations among strong and weak competing ligands, such as proteins in human serum, that determine dosages in drug therapies. The findings further enhance our understanding of the biophysical mode of action of the antibiotics and will help develop better treatments, including choice of drugs as well as dosages, against pathogens.
- Published
- 2014
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248. T11TS inhibits glioma angiogenesis by modulation of MMPs, TIMPs, with related integrin αv and TGF-β1 expressions.
- Author
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Singh MK, Bhattacharya D, Chaudhuri S, Acharya S, Kumar P, Santra P, Basu AK, and Chaudhuri S
- Subjects
- Animals, Blotting, Western, Endothelial Cells drug effects, Flow Cytometry, Fluorescent Antibody Technique, Glioma blood supply, Integrin alphaV metabolism, Matrix Metalloproteinases metabolism, Rats, Tissue Inhibitor of Metalloproteinases metabolism, Transforming Growth Factor beta1 metabolism, Angiogenesis Inhibitors pharmacology, Endothelial Cells metabolism, Glioma metabolism, Glycopeptides pharmacology, Neovascularization, Pathologic metabolism
- Abstract
During glioma development, angiogenesis plays a crucial role in growth and vascularization of primary brain tumors. T11 target structure (T11TS), a bioactive molecule, has been documented as an anti-neoplastic agent in glioma-induced rats and also in human glioma in vitro. This novel molecule induces apoptosis of tumor cells by way of immune potentiation and impairs the glioma cell cycle, but its role in glioma angiogenesis has not been worked out in detail. Matrix metalloproteinases (MMPs) are enzymes promoting tumor angiogenesis by enzymatically remodeling the extracellular matrix and altering surface protein expression such as integrin αv and the matrix-bound proteins like TGF-β1. The present study was formulated to assess the efficacy of T11TS in the modulations of MMP-2 and -9 and their endogenous inhibitors (TIMP-1 and TIMP-2) as well as modulations of integrin αv and TGF-β1 in glioma-induced rats and also on the phenotypic markers of endothelial cells (CD31 and CD34). The parameters used were zymography, western blot, and flow cytometric analyses. It was observed that T11TS administration significantly downregulates the expression of matrix metalloproteinase-2 and -9 along with its ligand integrin αv and upregulates TIMP-1 and TIMP-2. In situ immunofluorescence and FACS results revealed that T11TS administration decreased the expression of the phenotypic markers (CD31/PECAM1, CD34), inhibiting the cell grip and also downregulating TGF-β1 expression (ELISA) from microglia cells in the glioma microenvironment. These results suggest that T11TS suppresses the expression of positive angiogenic growth factors and potentiates the expression of negative regulators in glioma-associated endothelial cells (ECs), resulting in an anti-angiogenic effect on glioma-induced angiogenesis.
- Published
- 2014
- Full Text
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249. Outbreak in a haematology unit involving an unusual strain of glycopeptide-resistant Enterococcus faecium carrying both vanA and vanB genes.
- Author
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Marcadé G, Micol JB, Jacquier H, Raskine L, Donay JL, Nicolas-Viaud S, Rouveau M, Ribaud P, Dombret H, Leclercq R, and Cambau E
- Subjects
- Disease Outbreaks, Enterococcus faecium metabolism, France epidemiology, Glycopeptides therapeutic use, Hematologic Diseases drug therapy, Hematologic Diseases epidemiology, Hospital Units, Humans, Vancomycin Resistance drug effects, Bacterial Proteins genetics, Carbon-Oxygen Ligases genetics, Enterococcus faecium genetics, Glycopeptides pharmacology, Hematologic Diseases genetics, Vancomycin Resistance genetics
- Abstract
Objectives: To report an outbreak due to an unusual strain of Enterococcus faecium containing both the vanA and vanB genes, in France, where the rate of glycopeptide-resistant enterococci (GRE) is below 1%., Methods: Cases were patients infected or colonized with GRE on the haematology ward. Contact patients were screened by real-time PCR performed on rectal swabs. Clinical features were compared for GRE-positive and GRE-negative patients. GRE isolates were characterized by phenotypic and molecular methods including PFGE. Conjugation experiments were performed to identify van genetic support., Results: After the index patient presented a bacteraemia with vanA/vanB E. faecium, 56 contact patients were screened, 7 of whom were found to be GRE positive: 6 additional cases with vanA/vanB E. faecium and 1 with GRE carrying vanA only. PFGE confirmed the clonal relationship of the seven vanA/vanB E. faecium strains, whereas the vanA isolate was distinct. Only the vanA gene could be transferred to enterococcal recipients by conjugation, and it was probably localized on a mobile genetic element. All isolates were resistant to vancomycin (MIC > 256 mg/L) and teicoplanin (MIC = 24-32 mg/L), but were susceptible to tigecycline (MIC = 0.09 mg/L), linezolid (MIC = 0.75 mg/L) and daptomycin (MIC = 1-2 mg/L). Significant differences (P < 0.001) between carriers and non-carriers of GRE were observed for the median duration of hospitalization (57 days versus 16.5 days) and of neutropenia (40 days versus 6 days), the median number of antibiotics used (5 versus 1.5) and the duration of glycopeptide treatment (14.5 days versus 0 days)., Conclusions: vanA/vanB E. faecium strains, although rare, can emerge in the absence of previous outbreaks of vanA-GRE or vanB-GRE.
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- 2014
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250. Pulsed-focused ultrasound enhances boron drug accumulation in a human head and neck cancer xenograft-bearing mouse model.
- Author
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Wu CY, Chan PC, Chou LS, Chang CW, Yang FY, Liu RS, Chiou SH, Chen YW, Yen SH, and Wang HE
- Subjects
- Animals, Area Under Curve, Carcinoma, Squamous Cell diagnostic imaging, Carcinoma, Squamous Cell pathology, Cell Line, Tumor, Head and Neck Neoplasms pathology, Humans, Mice, Positron-Emission Tomography, Tissue Distribution drug effects, Tomography, X-Ray Computed, Tongue Neoplasms diagnostic imaging, Tongue Neoplasms pathology, Boron Compounds pharmacology, Glycopeptides pharmacology, Head and Neck Neoplasms diagnostic imaging, High-Intensity Focused Ultrasound Ablation, Xenograft Model Antitumor Assays
- Abstract
Purpose: This study aims to demonstrate that pulsed high-intensity focused ultrasound (pulsed-HIFU) may enhance the fructose-conjugated 4-borono-L-phenylalanine (BPA-Fr) accumulation in tumor lesion using (18)F-FBPA-Fr microPET scans., Procedures: To the mice bearing orthotopic SASC03 human tongue squamous carcinoma xenograft, a 2-min pulsed-HIFU was applied to tumor. Immediately after pulsed-HIFU treatment, (18)F-FBPA-Fr was intravenously injected, and biological characterizations including microPET imaging and biodistribution were conducted., Results: Both biodistribution studies and microPET imaging performed after intravenous injection of (18)F-FBPA-Fr revealed higher tumor uptake in HIFU-treated mice than that of the control. CD31 and Ki-67 histochemical staining of tumor sections and H&E staining of nearby normal tissues revealed no significant difference between the pulsed-HIFU-treated mice and the control., Conclusion: This study demonstrated that pulsed-HIFU was beneficial to the accumulation of boron drug in the head and neck tumor lesion and may enhance the therapeutic efficacy of clinical BNCT.
- Published
- 2014
- Full Text
- View/download PDF
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