Synthesis of a derivative of vancosamine, a component of the glycopeptide antibiotic vancomycin
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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/C39790000153Keywords:
Glycopeptide antibiotic
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Some Staphylococcus aureus isolates have glycopeptide minimal inhibitory concentrations (MICs) in the susceptible range but have subpopulations that grow on ⩾4 μg/mL vancomycin. Clinical laboratory methods for determining susceptibility have proven to be inadequate for detecting these strains. Among methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) clinical isolates, 149 (66.2%) of 225 and 17 (56.6%) of 30, respectively, grew on brain-heart infusion (BHI) medium containing 2 μg/mL vancomycin; 17 (7.5%) of the MRSA and 2 (6.6%) of the MSSA isolates grew on BHI screening plates containing 4 μg/mL vancomycin. One isolate grew on plates containing 6 μg/mL vancomycin. This isolate escaped detection by routine testing but had a vancomycin MIC of 6 μg/mL when tested in BHI medium. This isolate also had decreased Triton X-100–induced autolysis and killing when incubated in broth media containing vancomycin, properties accorded to glycopeptide-intermediate S. aureus isolates. These observations suggest that glycopeptide-intermediate–like S. aureus isolates are circulating undetected and that a continuum of decreased susceptibility exists in unselected isolates
Brain heart infusion
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Teicoplanin
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ABSTRACT The influence of reduced susceptibilities to glycopeptides on the activities of vancomycin and teicoplanin against an isogenic pair of clinical Staphylococcus aureus strains in experimental endocarditis was investigated. While vancomycin was similarly active against both strains, teicoplanin was approximately 100-fold less active against the resistant strain and selected for the emergence of more resistant subpopulations.
Teicoplanin
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Next-generation vancomycin analogues developed through semisynthetic modifications tackle vancomycin resistance and complex infections.
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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
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A strain of Enterococcus faecalis (A256) was isolated from the urine of a patient with urinary sepsis and was found to exhibit susceptibilities (micrograms per milliliter) to various glycopeptides as follows: vancomycin, 256; teicoplanin, 16; 62208, 512; 62211, 4; and 62476, 16. As judged by growth rates before and after exposure to sub-MICs of glycopeptides, vancomycin and 62476 induced self-resistance, 62208 and 62211 induced slight self-resistance, and teicoplanin did not induce self-resistance. Vancomycin induced cross-resistance to all other glycopeptides tested, as judged both in growth experiments and by direct measurement of inhibition of peptidoglycan synthesis in cells exposed to sub-MICs of vancomycin. Thus, the spectra of activity of the glycopeptides were not correlated with their patterns of induction. There was a correlation between the increased synthesis of a 39-kilodalton (kDa) protein located in the cytoplasmic membrane and the induction of resistance. Protoplasts of A256 were susceptible to inhibition of peptidoglycan synthesis by vancomycin at levels similar to those for susceptible strains. Vancomycin resistance was transferable on filters from the parent strain to E. faecalis JH2-2 at a frequency of about 10(-7), and the 39-kDa protein was also inducible by glycopeptides in these transconjugants. We conclude that A256 is resistant to glycopeptides by virtue of the synthesis of a 39-kDa cytoplasmic membrane protein, that this protein is probably involved in preventing access of the glycopeptides to their peptidoglycan targets, and that this resistance is transferable, probably by conjugation.
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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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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.
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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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