Glycopeptide-intermediate

Otvos et al. (27) adopted the Fmoc-pentafluorophenyl ester methodology and have applied O-deacetylated glycopeptide intermediates (170 and 171) for solid-phase synthesis of glycopeptides. In this way, the A-glycopep-tide (26) H-Gly-L-Lys-L-Ala-L-Tyr-L-Thr-L-Ile-L-Phe-L-... 

Robinson-Dunn B et al. Emergence of vancomycin resistance in Staph aureus. Glycopeptide-Intermediate S. aureus Working Group. N Engl J Med 1999 340 493-501. 

Staphylococcus aureus is one of the major resistant pathogens. Found on the mucous membranes and the skin of around a third of the population, it is extremely adaptable to antibiotic pressure. MRS A was first detected in the early 1960s and is now quite common in hospitals. Strains with intermediate (4-8 J,g/ml) levels of resistance, termed glycopeptide intermediate Staphylococcus aureus (GISA) or vancomycin intermediate Staphylococcus aureus (VISA), began appearing in the late 1990s the first documented strain with complete (> 16 ag/ml) resistance to vancomycin, termed vancomycin-resistant Staphylococcus aureus (VRSA), appeared in 2002. 

Vancomycin/glycopeptide intermediately resistant and methicillin-resistant S. aureus have been described in Japan, Europe, the Far East, and the USA. Some vancomycin-susceptible strains of S. aureus contain subpopulations with intermediate resistance to vancomycin (heterogeneous strains), and these may escape laboratory detection (93,94,97-99). 

Antimicrobial resistance of major consequence may be detected, e.g., the test is very useful in detecting glycopeptide-resistant enterococci and glycopeptide-intermediate Staphylococcus aureus and slow-growing pathogens such as Mycobacterium tuberculosis. Furthermore, it can be used for detecting extended spectrum P-lactamases. In conclusion, the E-test is a simple, accurate and reliable method to determine the MIC for a wide spectrum of infectious agents [33, 34]. 

A typical procedure calls for reaction of the hemiacetal donor with dicydohexyl carbodiimide and copper(I) chloride (0.1 equiv) at 80 °C, followed by an addition of the acceptor and continued heating. As an early demonstration of this protocol, oc-riboside 86 was prepared in moderate yield but with exclusive stereoselectivity [141]. Further measures were required for the glycosylation of monosaccharide acceptors, such as addition of p-toluenesulfonic add (0.1 equiv) to promote the formation of disaccharide 87 [144]. The method was more suitably applied to the synthesis of O-acyl glycopeptides, as evidenced by the formation of 88 in 60% yield [143,144]. Various peptides with non-nudeophilic side chains were found to be amenable to this stereoselective reaction. The [3-selectivity was suggested to arise from a preponderance of the a-isourea intermediate 85 in the activation step. 

Synthesis of glycopeptides in solution has been successfully applied in the preparation of glycopeptides of moderate lengths (see Sections 6.3.2 and 6.3.3). However, yields in solution synthesis are often only modest and isolation of intermediates makes the approach inconvenient. 

Anomeric Glycosyl Dianions as Intermediates in the Synthesis of C-Glycopeptides... 

The main function of the ester 34 in bacterial cells seems to be its participation in the biosynthesis of the glycopeptide cell-wall polymer. If this process is blocked, there results the accumulation of a high concentration of sugar nucleotide precursors in the cell. A number of these compounds have been isolated the simplest one is the ester of uridine 5 -pyrophosphate with N-acetylmuramic acid [2-acetamido-3-0-(D-l-carboxyethyl)-2-deoxy-D-glucose] (37), first obtained from Staphylococcus aureus cells that had been treated with penicillin7,151 or Gentian Violet.144 An intermediate in the biosynthesis of 37 was isolated and shown to be the 3 -enolpyruvate ether152,153 (38). 

Two biosynthetic intermediates of the vancomycin glycopeptides, SP-969 (2221) and SP-1134 (2222), are found in cultures of Amycolatopsis mediterranei (2018). This is the first reported isolation of linear biosynthetic intermediates of the vancomycin family. Monodechlorovancomycin 2223 is found for the first time in fermentation broths of Amycolatopsis orientalis (2019). The other monodechlorovancomycin was synthesized for comparison with 2223. 

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