Teicoplanin-type glycopeptides

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.

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... 

In addition to the vancomycin and teicoplanin CSPs, ristocetin A (Chirobiotic R) [289] and recently avoparcin [280] have been evaluated as novel chiral SOs and CSPs. It turned out that within the large family of macrocyclic antibiotics complementarity of enantioselectivity exists for different glycopeptides. As a consequence, very often it is possible to obtain a complete resolution by switching to a congeneric antibiotic CSP, if after optimization no baseline, but partial. separation can be achieved on a certain macrocyclic antibiotic type CSP (see Fig. 9.22). It can be expected that the enantioselectivity potential of closely related antibiotics will be further exploited in the future leading to an increase in the number of macrocyclic antibiotic type CSPs. 

Glycopeptide resistance in a cluster of three clinical isolates of vancomycin-resistant Enterococcus faecium was due to vanD, which was located on the chromosome and was not transferable to other enterococci These isolates were indistinguishable but differed from the strain in which vanD-mediated resistance has been reported previously (102). A type of acquired glycopeptide resistance, named vanE, has been characterized in E. faecalis BM 4405. It results in low-level resistance of vancomycin but susceptibility to teico-planin (103). Defects in penicillin-binding protein 4 result in a distorted peptidoglycan composition of the cell of vancomycin-resistant and teicoplanin-resistant laboratory mutants of S. aureus and are suggested to be part of the mechanism of glycopeptide resistance in these microbes (104). 

Tesarova and Bosakova [58] proposed an HPLC method for the enantio-selective separation of some phenothiazine and benzodiazepine derivatives on six different chiral stationary phases (CSPs). These selected CSPs, with respect to the structure of the separated compounds, were either based on b-CD chiral selectors (underivatized (J>-CD and hydroxypropyl ether (3-CD) or on macrocyclic antibiotics (vancomycin, teicoplanin, teicoplanin aglycon and ristocetin A). Measurements were carried out in a reversed-phase separation mode. The influence of mobile phase composition on retention and enantio-selective separation was studied. Enantioselective separation of phenothiazine derivatives, including levopromazine (LPZ), promethazine and thioridazine, was relatively difficult to achieve, but it was at least partly successful with both types of CSPs used in this work (CD-based and glycopeptide-based CSP), except for levomepromazine for which only the [CCD-based CSP was suitable. 

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.

Fig. 7.17 Complementary chiral recognition profiles of glycopeptide-type CSPs. (A) N-CBZ-norvaline on vancomycin (left) and teicoplanin (right). Mobile phase methanol/1 % triethy-lammonium acetate (20/80 v/v) pH 4.1.

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