Vancomycin-type glycopeptides

New vancomycin-type glycopeptide antibiotics are in clinical trials to combat methicillin-resistant bacteria (2612, 2613) such as the deadly Staphylococcus aureus (2614). For the first time, extracts of marine algae indigenous to Japan have shown activity against methicillin-resistant Staphylococcus aureus bacteria (2615, 2661). The therapeutic use of iodine has been rejuvenated (2616). For example, in the treatment of cyclic mastalgia (2617). 

Scheme 2-1. Structures of important vancomycin-type glycopeptide antibiotics.

Scheme 2-4. (a) Binding of vancomycin to the Lys-D-Ala-D-Ala peptide motive with Hve hydrogen bonds, (b) Dimerization of vancomycin-type glycopeptide antibiotics (e.g., chloroeremomycin) over six hydrogen bonds. Because vancomycin lacks a vancosamine sugar at AA6, it interacts only over four hydrogen bonds. 

Scheme 2-9. Semisynthetic modifications of vancomycin-type glycopeptide antibiotics, (a) Alterations and modifications of amino acids, (b) Attachment of molecules to the amino groups, to the carboxy groups, and to phenolic carbohydrate functionalities. Similar modifications have been performed for antibiotics of the teicoplanin-type.

However, its a-carboxylate is often amidated or linked to an additional amino acid and in Microbacterium lacticum y-D-Glu is replaced by f/rreo-S-hydroxy-D-glutamic acid (3-Hyg). Most variation is found in position 3. If m-DAP (D,L-configuration) is incorporated, the L center is found in the pentapeptide chain and the D center in the side chain. Positions 4 and 5 (D-Ala-D-Ala) were for a long time thought to be invariant. However, the incidence of bacterial resistance to vancomycin-type glycopeptide antibiotics which recognize specifically the A-acyl-D-Ala-D-Ala terminus led to the discovery that these resistant strains contain altered substituents at position 5 as indicated in Fig. 16b [194,195,196]. 

Selected structures of vancomycin-type glycopeptide antibiotics belonging to groups l-IV... 

Bischoff, D., S. Pelzer, B. Bister, G.J. Nicholson, S. Stockert, M. Schirle et al. (2001). The biosynthesis of vancomycin-type glycopeptide antibiotics—The order of the cyclization steps. Angew. Chem. Int. Ed. 40, 4688-4691. 

Trauger J W, Walsh C T (2000). Heterologous expression in Escherichia coli of the first module of nonribosomal peptide synthase for chloroeremomycin, a vancomycin-type glycopeptide antibiotic. Proc. Natl. Acad. 97 3112-3117. 

Bisehoff D, Pelzer S, Bister B, Nieholson GJ, Stock-ert S, Sehirle M, Wohlleben W, Jung G, Sussmuth RD (2001) The biosynthesis of vancomycin-type glycopeptide antibiotics the order of the cycliza-tion steps. Angew Chem Int Ed Engl 40 4688-4691... 

Bischolf D, Bister B, Bertazzo M, Pfeifer V, Steg-mann E, Nicholson GJ, Keller S, Pelzer S, Wohl-leben W, Sussmuth RD (2005) The biosynthesis of vancomycin-type glycopeptide antibiotics—a model for oxidative side-chain cross-linking by oxygenases coupled to the action of peptide synthetases. ChemBioChem 6 267-272... 

RD (2001) The biosynthesis of vancomycin-type glycopeptide antibiotics—the order of the cycliza-tion steps. Angew Chem Int Ed 40 4688-4691... 

Siissmuth RD, Pelzer S, Nicholson G, Walk T, Wohlleben W, Jung G (1999) New Advances in the Biosynthesis of Glycopeptide Antibiotics of the Vancomycin Type from Amycolatopsis mediterranei. Angew Chem Int Ed 38 1976... 

NMR of Glycopeptide (Vancomycin-Type) Antibiotics Structure and Interaction with... 

Figure 2.14 Mutasynthesis of glycopeptide antibiotics vancomycin, 3,5-dihydroxyphenyl-glycine (DPG), and vancomycin-type antibiotics.

For most free amino acids and small peptides, a mixture of alcohol with water is a typical mobile phase composition in the reversed-phase mode for glycopeptide CSPs. For some bifunctional amino acids and most other compounds, however, aqueous buffer is usually necessary to enhance resolution. The types of buffers dictate the retention, efficiency and - to a lesser effect - selectivity of analytes. Tri-ethylammonium acetate and ammonium nitrate are the most effective buffer systems, while sodium citrate is also effective for the separation of profens on vancomycin CSP, and ammonium acetate is the most appropriate for LC/MS applications. 

Acquired resistance to the glycopeptides is transposon-mediated and has so far been largely confined to the enterococci. This has been a problem clinically because many of these strains have been resistant to all other antibiotics and were thus effectively untreatable. Fortunately, the enterococci are not particularly pathogenic and infections have been confined largely to seriously ill, long-term hospital patients. Two types of acquired glycopeptide resistance have been described (Woodford et al. 1995). The VanA phenotype is resistant to vancomycin and teicoplanin, whereas VanB is resistant... 

Tertiary treatment implemented Genes encoding D-alanine D-alanine ligases with a broad substrate specificity confer inducible resistance to the glycopeptides antibiotics, as vancomycin World Health Organization Wild-type... 

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