Chemistry Reference
In-Depth Information
bacterial isolates causes severe treatment problems especially with elderly people and
immunosuppressed patients. The molecular mechanism of enterococcal resistance is
based on the change of the D-Ala-D-Ala peptide of the bacterial cell wall biosynthesis
to D-Ala-D-Lac (vanA/B resistance) or D-Ala-D-Ser (vanC resistance). The well-
investigated vanA/B phenotypes
30-34
are based on five genes (vanS, vanR, vanH,
vanA, and vanX). VanS is a vancomycin-dependant sensor kinase, which induces
the cleavage of D-Ala-D-Ala-dipeptides (vanX) and at the same time promotes the
formation of D-Ala-D-Lac (vanA). The increased amounts of lactate necessary for
cell wall biosynthesis are formed from pyruvate by the action of ketoreductase
vanH. The glycopeptide resistance on the molecular level is based on the loss of
one hydrogen bond combined with the electronic repulsion of two oxygen atoms
between the lactate oxygen and the glycopeptide carbonyl (Scheme 2-5). As a result
of the alteration of cell wall biosynthesis, the affinity of glycopeptides to D-Ala-D-
Lac is
1000-fold decreased
35
and thus is no longer useful as an antibiotic.
36
For the
D-Ala-D-Ser-modification (vanC resistance),
37,38
it is assumed that glycopeptide
binding is less tight because of steric reasons.
39
As a consequence, both cell wall bio-
synthesis alterations lead to a markedly reduced susceptibiliy toward glycopeptide
antibiotics, whereas some strains remain sensitive to teicoplanin.
Thus far, the reasons for glycopeptide-resistance of S. aureus strains are not
entirely clear. It is assumed that an increased biosynthesis of cell wall precursors
combined with a thickened cell wall are the likely reasons.
40
However, also the
transferance
of
enterococcal
resistance
to
S.
aureus
has
been
shown
in
the
“wild-type”
HO
NH
3
O
O
H
N
Me
O
Me
OH
OH
H
3
N
N
H
O
O
NH
O
R
CH
2
OH
O
O
Cl
vanA/B
O
O
O
O
Cl
H
3
N
O
HO
OH
N
H
O
O
O
H
N
H
N
H
N
NH
O
R
N
H
NH
Me
O
H
H
H
H
O
O
NH
2
H
O
O
H
vanC
NH
2
O
O
O
2
C
H
N
OH
H
3
N
N
H
O
OH
HO
NH
O
O
O
R
OH
H
3
N
O
N
H
O
NH
O
R
Scheme 2-5. Molecular basis of enterococcal vanA/B- and vanC-glycopeptide resistance.
Interaction of vancomycin with D-Ala-D-Lac. The lactate ester bond leads to a lowered
ligand binding affinity by loss of one hydrogen bond and electronic repulsion (solid arrow).
Search WWH ::
Custom Search