Vancomycin Resistance in Gram-Positive Cocci
0
Antibacte riens, Institut Pasteur
,
25, rue du Docteur Roux, 75724 Paris, Cedex 15
,
France
1
Patrice Courvalin Unite des Agents Antibacte riens, Institut Pasteur
,
Paris
,
France
The first vancomycin-resistant clinical isolates of Enterococcus species were reported in Europe in 1988. Similar strains were later detected in hospitals on the East Coast of the United States. Since then, vancomycin-resistant enterococci have spread with unexpected rapidity and are now encountered in hospitals in most countries. This article reviews the mode of action and the mechanism of bacterial resistance to glycopeptides, as exemplified by the VanA type, which is mediated by transposon Tn1546 and is widely spread in enterococci. The diversity, regulation, evolution, and recent dissemination of methicillin-resistant Staphylococcus aureus are then discussed.
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MODE OF ACTION OF VANCOMYCIN
The synthesis of peptidoglycan in the production of
bacterial cell walls requires several steps. In the
cytoplasm, a racemase converts l-alanine to d-alanine
(dAla), and then 2 molecules of d-Ala are joined by a
ligase, creating the dipeptide d-Ala-d-Ala, which is then
added to uracil
diphosphateN-acetylmuramyl-tripeptide to form uracil
diphosphateN-acetylmuramyl-pentapeptide. Uracil
diphosphateN-acetylmuramyl-pentapeptide is bound to the undecaprenol lipid carrier,
which, after the addition of GlcNAc from uracil
diphosphateGlcNAc, allows translocation of the
precursors to the outer surface of the cytoplasmic
membrane. N-acetylmuramyl-pentapeptide is then
incorporated into nascent peptidoglycan by
transglycosylation and allows the formation of cross-bridges by
transpeptidation [5].
Vancomycin binds with high affinity to the
d-Alad-Ala C-terminus of the pentapeptide, thus blocking
the addition of late precursors by transglycosylation to
the nascent peptidoglycan chain and preventing
subsequent cross-linking by transpeptidation (figure 1) [5].
Vancomycin does not penetrate into the cytoplasm;
therefore, interaction with its target can take place only
after translocation of the precursors to the outer surface
of the membrane.
MECHANISM OF RESISTANCE TO
VANCOMYCIN
Because vancomycin does not interact with cell wall
biosynthetic enzymes but forms complexes with
peptidoglycan precursors, its activity is not determined by the
affinity for a target enzyme but by the substrate specificity
of the enzymes that determine the structure of
peptidoglycan precursors. Resistance to vancomycin is due to
the presence of operons that encode enzymes (1) for
synthesis of low-affinity precursors, in which the
C-terminal d-Ala residue is replaced by d-lactate (d-Lac) or
d-serine (d-Ser), thus modifying the vancomyin-binding
target; and (2) for elimination of the high-affinity
precursors that are normally produced by the host, thus
removing the vancomycin-binding target [6].
Target modification. VanA-type resistance, which
is characterized by inducible high levels of resistance
to vancomycin and teicoplanin (table 1), was the first
type of resistance described and is mediated by
transposon Tn1546 and elements closely related to it. The
transposon encodes a dehydrogenase (VanH), which
reduces pyruvate to d-Lac, and the VanA ligase, which catalyzes
the formation of an ester bond between d-Ala and d-Lac (figure
2) [6]. The resulting d-Ala-d-Lac depsipeptide replaces the
dAla-d-Ala dipeptide in peptidoglycan synthesis, a substitution
that decreases the affinity of the molecule for glycopeptides
considerably [7].
The VanC resistance phenotype was described first in
Enterococcus gallinarum [8] and then in the Enterococcus
casseliflavusEnterococcus flavescens [9] species, which possess
intrinsic low levels of resistance to vancomycin and are susceptible
to teicoplanin (table 1). Three genes are required for
VanCtype resistance (figure 3): vanT encodes the VanT
membranebound serine racemase, which produces d-Ser; the vanC gene
product VanC synthesizes d-Ala-d-Ser, which replaces
d-Alad-Ala in late peptidoglycan precursors; and vanXYc encodes
the VanXYC protein, which possesses both D,D-dipeptidase and
D,D-carboxypeptidase activities and allows hydrolysis of
precursors ending in d-Ala [10]. Substitution of the ultimate
dAla by a d-Ser results in steric hindrance that reduces its affinity
for vancomycin [11].
Removal of the susceptible target. The simultaneous
production of precursors ending in d-Ala or d-Lac does not lead
Vancomycin
Teicoplanin
Conjugation
Expression
Location Modified target High, VanA
Positive
Inducible
S26 CID 2006:42 (Suppl 1) Courvalin
NOTE. d-Ala-d-Lac, d-alanine-d-lactate; d-Ala-d-Ser, d-alanine-d-serine.
Acquired resistance level, type
Positive
Inducible
Negative
Constitutive
Chromosome
Low VanG VanE 16
Positive
Inducible
Chromosome
Negative
Inducible
Chromosome
Intrinsic resistance,
low level,
type VanC1/C2/C3
Negative
Constitutive Inducible
Chromosome
to resistance [12]. Under these conditions, binding of
g (...truncated)