Requirement of the VanY and VanX <scp>D</scp>,<scp>D</scp>‐peptidases for glycopeptide resistance in enterococci

Arthur, Michel; Depardieu, Florence; Cabanié, Lucien; Reynolds, Peter E.; Courvalin, Patrice

doi:10.1046/j.1365-2958.1998.01114.x

Cited by 105 publications

(116 citation statements)

References 35 publications

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“…1) that is required for resistance (7). In the absence of vancomycin, JH2-2::I was as competitive as JH2-2::S, demonstrating that the biological cost of glycopeptide resistance in enterococci is negligible when noninduced.…”

Section: Discussionmentioning

confidence: 92%

“…Acquired resistance to the glycopeptides vancomycin and teicoplanin in enterococci is due to the synthesis of modified peptidoglycan precursors ending in D-alanyl-D-lactate (D-Ala-D-Lac), to which glycopeptides exhibit low binding affinities, together with elimination of the high-affinity D-Ala-D-Ala ending precursors (5,6 (7). Expression of resistance is induced by vancomycin and regulated by a two-component regulatory system composed of a sensor (VanS B ) and a regulator (VanR B ) that acts as a transcriptional activator (8).…”

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confidence: 99%

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Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci

Foucault

Depardieu

Courvalin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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105

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Inducible vancomycin resistance in enterococci is due to a sophisticated mechanism that combines synthesis of cell wall peptidoglycan precursors with low affinity for glycopeptides and elimination of the normal target precursors. Although this dual mechanism, which involves seven genes organized in two operons, is predicted to have a high fitness cost, resistant enterococci have disseminated worldwide. We have evaluated the biological cost of VanB-type resistance due to acquisition of conjugative transposon Tn1549 in Enterococcus faecium and Enterococcus faecalis. Because fitness was dependent on the integration site of Tn1549, an isogenic set of E. faecalis was constructed to determine the cost of inducible or constitutive expression of resistance or of carriage of Tn1549. A luciferase gene was inserted in the integrase gene of the transposon to allow differential quantification of the strains in cocultures and in the digestive tract of gnotobiotic mice. Both in vitro and in vivo, carriage of inactivated or inducible Tn1549 had no cost for the host in the absence of induction by vancomycin. In contrast, induced or constitutively resistant strains not only had reduced fitness but were severely impaired in colonization ability and dissemination among mice. These data indicate that tight regulation of resistance expression drastically reduces the biological cost associated with vancomycin resistance in Enterococcus spp. and accounts for the widespread dissemination of these strains. Our findings are in agreement with the observation that regulation of expression is common in horizontally acquired resistance and represents an efficient evolutionary pathway for resistance determinants to become selectively neutral.O ne of the key parameters influencing emergence and stability of antibiotic resistance is the biological cost that resistance determinants impose on cell growth (1). Many studies have shown that resistant bacteria are less fit than their susceptible counterpart, although they can acquire compensatory mutations that restore fitness (2). However, most reports have dealt with resistance due to chromosomal mutations, and fewer have evaluated the fitness change due to acquisition of mobile genetic elements conferring clinically relevant resistance (3).Enterococci are commensals of the intestine of humans and animals but can also be opportunistic pathogens. This bacterial genus has acquired resistance to many antibiotics, and glycopeptides are often the ultimate treatment of infections due to these The vanA operon is part of transposon Tn1546, which is often carried by self-transferable plasmids, accounting for its spread (9). Dissemination of VanB-type resistance results from the spread of conjugative transposon Tn1549 (10) located on plasmids or in the chromosome. Despite the sophisticated dual mechanism of resistance, glycopeptide-resistant enterococci have disseminated worldwide.Two studies have investigated the burden of glycopeptide resistance imposed on enterococci, with conflicting results. A fitness di...

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci

Foucault

Depardieu

Courvalin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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105

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“…The vanF genotype has been also described in the biopesticide Paenibacillus popilliae (Patel et al, 2000). Glycopeptide resistance is due to the synthesis of modified peptidoglycan precursors with low affinity for these antibiotics (Arthur et al, 1996a) (David et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Genomic and expression analysis of the vanG-like gene cluster of Clostridium difficile

et al. 2013

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Primary antibiotic treatment of Clostridium difficile intestinal diseases requires metronidazole or vancomycin therapy. A cluster of genes homologous to enterococcal glycopeptides resistance vanG genes was found in the genome of C. difficile 630, although this strain remains sensitive to vancomycin. This vanG-like gene cluster was found to consist of five ORFs: the regulatory region consisting of vanR and vanS and the effector region consisting of vanG, vanXY and vanT. We found that 57 out of 83 C. difficile strains, representative of the main lineages of the species, harbour this vanG-like cluster. The cluster is expressed as an operon and, when present, is found at the same genomic location in all strains. The vanG, vanXY and vanT homologues in C. difficile 630 are co-transcribed and expressed to a low level throughout the growth phases in the absence of vancomycin. Conversely, the expression of these genes is strongly induced in the presence of subinhibitory concentrations of vancomycin, indicating that the vanG-like operon is functional at the transcriptional level in C. difficile. Hydrophilic interaction liquid chromatography (HILIC-HPLC) and MS analysis of cytoplasmic peptidoglycan precursors of C. difficile 630 grown without vancomycin revealed the exclusive presence of a UDP-MurNAc-pentapeptide with an alanine at the C terminus. UDP-MurNAc-pentapeptide [D-Ala] was also the only peptidoglycan precursor detected in C. difficile grown in the presence of vancomycin, corroborating the lack of vancomycin resistance. Peptidoglycan structures of a vanG-like mutant strain and of a strain lacking the vanG-like cluster did not differ from the C. difficile 630 strain, indicating that the vanGlike cluster also has no impact on cell-wall composition.

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“…Resistance by this mechanism is mediated by two related gene clusters, vanA and vanB, that encode a dehydrogenase and a ligase for synthesis of DAla-D-Lac and two DD-peptidases for elimination of peptidoglycan precursors ending in D-Ala ( Fig. 1) (Bugg et al, 1991;Arthur et al, 1998). Transcription of the vanA and vanB clusters is regulated by the VanRS and VanR,S, two-component regulatory systems (Arthur et al, 1992;Evers & Courvalin, 1996).…”

Section: Introductionmentioning

confidence: 99%

Regulated interactions between partner and non-partner sensors and response regulators that control glycopeptide resistance gene expression in enterococci

Arthur¹,

Depardieu²,

Courvalin³

1999

Microbiology

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genes, respectively. Under non-inducing conditions, activation of VanR by cross-talk was blocked by the presence of a multicopy plasmid carrying Pw Presence of the high-affinity VanR-binding sites of the regulatory region of PH on the multicopy vector probably sequestered VanR, thereby preventing autoactivation of the PR promoter. Under such circumstances, stimulation of the host kinase by glycopeptides or moenomycin was required for expression of the resistance genes.

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Requirement of the VanY and VanX D,D‐peptidases for glycopeptide resistance in enterococci

Cited by 105 publications

References 35 publications

Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci

Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci

Genomic and expression analysis of the vanG-like gene cluster of Clostridium difficile

Regulated interactions between partner and non-partner sensors and response regulators that control glycopeptide resistance gene expression in enterococci

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