Modification of peptidoglycan precursors is a common feature of the low-level vancomycin-resistant VANB-type Enterococcus D366 and of the naturally glycopeptide-resistant species Lactobacillus casei, Pediococcus pentosaceus, Leuconostoc mesenteroides, and Enterococcus gallinarum
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The biochemical basis for the acquired or natural resistance of various gram-positive organisms to glycopeptides was studied by high-pressure liquid chromatographic analysis of their peptidoglycan UDP-MurNAc-peptide precursors. In all cases, resistance was correlated with partial or complete replacement of the C-terminal D-Ala-D-Ala-containing UDP-MurNAc-pentapeptide by a new precursor with a modified C terminus. Nuclear magnetic resonance analysis by sequential assignment showed that the new precursor encountered in Enterococcus faecium D366, a strain belonging to the VANB class, which expresses low-level resistance to vancomycin, was UDP-MurNAc-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-lactate, identical to that previously found in the VANA class, which expresses high-level resistance to vancomycin. High-pressure liquid chromatographic analyses, composition determinations, and digestion by R39 D,D-carboxypeptidase demonstrated the exclusive presence of the new precursor in Lactobacillus casei and Pediococcus pentosaceus, which are naturally highly resistant to glycopeptides. The low-level natural resistance of Enterococcus gallinarum to vancomycin was found to be associated with the synthesis of a new precursor identified as a UDP-MurNAc-pentapeptide containing a C-terminal D-serine. The distinction between low and high levels of resistance to glycopeptides appeared also to depend on the presence or absence of a substantial residual pool of a D-Ala-D-Ala-containing UDP-MurNAc-pentapeptide.Keywords:
Enterococcus faecium
Lactobacillus casei
Pentapeptide repeat
Pediococcus
Glycopeptide antibiotic
Extensionality
N-beta-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-asparaginyl peptides [Asn(GlcNAc)] corresponding to T-helper cell determinants were synthesized on solid-phase. Various amino-terminal- and carbohydrate-protecting groups were used on the glycosylated asparagine residue which was coupled to the peptide chain. We found that coupling rates decreased with increased size of the protected carbohydrate part of the acylating agent. Double couplings with an O-unprotected saccharide, as in Fmoc-Asn(GlcNAc)-OH resulted in acceptable coupling rates even with a synthetically difficult sequence corresponding to the T-cell epitopic peptide from the C-terminus of pigeon cytochrome c. The observed coupling rates on this peptide as well as on a T-cell epitopic pentapeptide, derived from the rabies virus N-protein, were comparable to those of conventional solid-phase peptide syntheses. The Fmoc-Asn(GlcNAc)-OH used can be prepared easily from commercially available components. The described glycopeptides will be used to probe effects of N-glycosylation on the immune recognition of viral glycoproteins.
Pentapeptide repeat
Solid-Phase Synthesis
Peptide Synthesis
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Sequence (biology)
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Teicoplanin
Glycopeptide antibiotic
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Teicoplanin is a glycopeptide antibiotic that has proven efficacy against Gram‐positive bacteria and is in clinical trials. It is distinguished from vancomycin‐type glycopeptides antibiotics by side chain modifications, which have been shown to contribute to its improved efficacy and superior pharmacokinetic profile. Our research aims to study the biosynthetic mechanisms of teicoplanin, which will likely lead to the development of new glycopeptide derivatives. Here we present high resolution crystal structures of several enzymes that modify teicoplanin side chains during its biosynthesis. The structures provide insights into the active residues of these enzymes and suggest possible mechanisms of modifying glycopeptides antibiotics.
Teicoplanin
Glycopeptide antibiotic
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The antibiotic glycopeptide class, of which vancomycin is the original compound, has received due attention over the past few decades in search of antibiotics to overcome resistances developed by bacteria. Crucial for the understanding and further development of glycopeptides that possess desired antibacterial effects is the determination of their conformational behavior, as this sheds light on the mechanism of action of the compound. Among others, vibrational optical activity (VOA) techniques (vibrational circular dichroism and Raman optical activity) can be deployed for this, but the question remains to what extent these spectroscopic techniques can provide information concerning the molecular class under investigation. This contribution takes the last hurdle in the search for the capabilities of the VOA techniques in the conformational analysis of the antibiotic glycopeptide class by extending research that was previously conducted for vancomycin toward its three derivatives: oritavancin, dalbavancin, and teicoplanin. The principal information that can be drawn from VOA spectra is the conformation of the rigid cyclic parts of the glycopeptides and the aromatic rings that are part hereof. The addition or removal of carbohydrates does not induce noticeable VOA spectral responses, preventing the determination of the conformation they adopt.
Teicoplanin
Glycopeptide antibiotic
Dalbavancin
Raman optical activity
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Teicoplanin
Glycopeptide antibiotic
Dalbavancin
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Fosfomycin
Nephrotoxicity
Glycopeptide antibiotic
Teicoplanin
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Glycopeptide antibiotic
Degradation
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The structure of the two factors of the novel glycopeptide antibiotic A40926 have been determined using a combination of FAB-MS, GC-MS and 1H n.m.r. studies. A40926 Is a member of the vancomycin family of antibiotics and is structurally related to teicoplanin, A35512B and aridicin.
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Glycopeptide antibiotic
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The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low active des-(N-methyl-d-leucyl)eremomycin (5), eremomycin aglycon (6), des-(N-methyl-d-leucyl)eremomycin aglycon (7), and a teicoplanin degradation product TB-TPA (8). All hydrophobic amides of 1, 3, 4, and 6 were almost equally active against glycopeptide-resistant enterococci (GRE) [minimum inhibitory concentrations (MIC) ≤ 4 μg/mL] and had better activity against Gram-positive strains sensitive to glycopeptides than against GRE. Extensive degradation of the glycopeptide framework in amides of 7 and 8 led to a decrease of anti-GRE activity (MIC = 16−64 μg/mL), and for these derivatives MIC values for bacterial strains sensitive and resistant to glycopeptides were very close. These results suggest that in sensitive bacteria two mechanisms of action are operating for the hydrophobic derivatives of glycopeptide antibiotics with the nondamaged peptide coreinteraction with the d-Ala-d-Ala moiety and the inhibition of bacterial membrane bound enzymatic reactions, whereas for GRE lacking the d-Ala-d-Ala fragment, only the second mechanism is operating. It appears that a minimal glycopeptide core is required for activity, and that more extensive degradation results in a serious decrease of antibacterial activity.
Teicoplanin
Glycopeptide antibiotic
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T. T. Thang, F. Winternitz, A. Olesker, A. Lagrange and G. Lukacs, J. Chem. Soc., Chem. Commun., 1979, 153 DOI: 10.1039/C39790000153
Glycopeptide antibiotic
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