THE CHEMISTRY AND BIOLOGY OF VANCOMYCIN AND OTHER GLYCOPEPTIDE ANTIBIOTIC DERIVATIVES - Medicinal Chemistry of Bioactive Natural Products - page 40

The peptidoglycan layer confers mechanical stability to the cell wall of the bacteria.
An important intermediate of the peptidoglycan biosynthesis is the GlcNAc- MurNAc-
L-Ala-D-g-Gln-L-Lys-D-Ala-D-Ala peptide (muramyl-pentapeptide), which is in
its lipid-carrrier bound form transglycosylated to a linear polysaccharide. The linear
polysaccharide is then cross-linked to peptidoglycan by transpeptidation reactions.
Perkins observed 20 that vancomycin binds to the Lys-D-Ala-D-Ala peptide motif of
bacterial cell wall intermediates. This observation was later investigated on a mole-
cular level by NMR 21,22 and by x-ray crystallographic studies. 23,24
As mentioned, the primary antibiotic effect of glycopeptide antibiotics is based
on the binding to the D-Ala-D-Ala dipeptide motive of the bacterial cell wall
biosynthesis. In contrast to penicillin, which covalently binds to an enzymatic tar-
get, glycopeptide antibiotics represent substrate binders that shield the substrate
from transpeptidation but also from transglycosylation reactions. On the molecular
level, five hydrogen bonds between the peptidic backbones of the D-Ala-D-Ala
ligand and the glycopetide receptor (Scheme 2-4) contribute to a tight binding
with binding constants in the range of 10 5 M 1 to 10 6 M 1 . 25 The microheterogeni-
city found for glycopeptides, that is structural variations in the degree of glycosyla-
tion, N-terminal methylation, chlorination, and differences in the length of fatty
acid side chains, result in varying antibiotic activities of these derivatives.
Of some importance is the ability of most glycopeptides to form dimers
(e.g., eremomycin) 26 or to insert into bacterial membranes (e.g., teicoplanin). 27
Dimer formation is strongly dependent on the nature of the carbohydrates attached
to the aglycon and on the attachment site of these residues. Chloroeremomycin
(Scheme 2-1), which contains the amino sugar 4-epi-vancosamine bound to AA6,
forms dimers with six hydrogen bonds (Scheme 2-4), whereas vancomycin shows a
weak dimerization tendency by the formation of only four hydrogen bonds. The
dimerization behavior originally observed with NMR has also been confirmed by
x-ray crystallography. 17,23 Furthermore, cooperativity effects of ligand bound gly-
copeptides in dimerization have been found as well as a stronger binding of ligands
through glycopeptide dimers. 28 In constrast, for type IV-glycopeptide antibiotics,
membrane anchoring is assumed, which forms an ''intramolecular'' complex
with its target peptide on the cell surface. 27-29 An excellent review, which
highlights details of the mode of action of glycopeptide antibiotics on a molecular
level, has been published by Williams and Bardsley. 5 In summary, the binding of
D-Ala-D-Ala peptides can be considered as the primary and main effect for antibio-
tic activity of naturally occuring glycopeptide antibiotics. Dimerization and
membrane anchoring mechanisms are secondary effects, which only modulate
the antibiotic activity. This consideration is true, if no other inhibiting effects
have to be taken into account.

2.4 GLYCOPEPTIDE RESISTANCE

Over the past decade the emergence of resistant enterococci and S. aureus strains has
been observed in clinics. Already, nowadays, the increase of glycopeptide-resistant