Vancomycin-type antibiotic

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.

Recktenwald J, Shawky R, Puk O, Pfennig F, Keller U, Wohlleben W, Pelzer S (2002) Nonribosomal biosynthesis of vancomycin-type antibiotics a hep-tapeptide backbone and eight peptide synthetase modules. Microbiology 148 1105-1118... 

Some P450s are able to catalyze oxidative phenol coupling, a reaction usually carried out by peroxidases. Three independent P450 monooxygenases with such activity have been shown to be involved in the synthesis of vancomycin-type antibiotics in Amycolatopsis balhimycina [67]. 

Structure-activity relationship studies of vancomycin-type glyco-peptide antibiotics (e.g. vancomycin 172) have shown that removal of chlorine reduces the activity by ten-fold [133]. 

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). 

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... 

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.

Another important Type 111 PKS is the dihydroxyphenylacetic acid synthase (DHPAS) encoded by the balhimycin gene cluster ia Amycolatopsis mediterraneiP DHPA is the precursor of the nonproteinogenic amino acid 5 -3,5-dihydroxyphenyl-glycine (DHPG), which is found in vancomycin-related antibiotics. DHPAS condenses four malonyl-CoAs to yield an acetate-primed tetraketide, and catalyze the C6-C1 Claisen condensation observed in CHS. 

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... 

Fig. 7.15 Chemical structures of the glycopeptide-type antibiotics vancomycin, teicoplanin and ristocetin A. For teicoplanin the prevalent derivative (A2-2, 85%) of the teicoplanin complex is shown.

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... 

Scheme 3 Identification of a Vancomycin-type receptor overcoming antibiotic resistance...

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... 

Type I IgE Anaphylaxis, urticaria P-Lactam antibiotics penicillins (primarily), cephalosporins, carbapenems Non-fl-lactam antibiotics sulfonamides, vancomycin Others insulin, heparin... 

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