Vancomycin Resistance in Gram-Positive Cocci

Clinical Infectious Diseases, Jan 2006

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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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. - 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)


This is a preview of a remote PDF: https://cid.oxfordjournals.org/content/42/Supplement_1/S25.full.pdf

Patrice Courvalin. Vancomycin Resistance in Gram-Positive Cocci, Clinical Infectious Diseases, 2006, pp. S25-S34, 42/Supplement 1, DOI: 10.1086/491711