Peptidoglycan Cross-Linking Activity of
            <scp>l</scp>
            ,
            <scp>d</scp>
            -Transpeptidases from Clostridium difficile and Inactivation of These Enzymes by β-Lactams

Sütterlin, Laetitia; Edoo, Zainab; Hugonnet, Jean-Emmanuel; Mainardi, Jean–Luc; Arthur, Michel

doi:10.1128/aac.01607-17

Cited by 27 publications

(46 citation statements)

References 24 publications

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“…(Peltier et al ., ) and Sutterlin et al . (Sutterlin et al ., ) identified and purified three L,D‐transpeptidases, CD630_29630 (Ldt Cd1 ), CD630_27130 (Ldt Cd2 ) and CD630_30070 (Ldt Cd3 ), in C. difficile 630. Among them, Ldt Cd2 and Ldt Cd3 can catalyse the formation of 3 → 3 cross‐links (L,D‐transpeptidase activity), while Ldt Cd1 displays only L,D‐carboxypeptidase activity (Sutterlin et al ., ).…”

Section: Discussionmentioning

confidence: 99%

“…(Sutterlin et al ., ) identified and purified three L,D‐transpeptidases, CD630_29630 (Ldt Cd1 ), CD630_27130 (Ldt Cd2 ) and CD630_30070 (Ldt Cd3 ), in C. difficile 630. Among them, Ldt Cd2 and Ldt Cd3 can catalyse the formation of 3 → 3 cross‐links (L,D‐transpeptidase activity), while Ldt Cd1 displays only L,D‐carboxypeptidase activity (Sutterlin et al ., ). They demonstrated that the inactivation of the ldt Cd1 , ldt Cd2 and ldt Cd1 plus ldt Cd2 could result in a 22%, 15% and 28% decrease in the proportion of muropeptide dimers containing 3 → 3 cross‐links respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, we did not detect a significant MIC difference for β-lactam antibiotics between the cwp22 mutant and R20291 (data not shown), which indicates that some other enzyme could also play the same role of L,D-transpeptidase in R20291. Recently, Peltier et al (Peltier et al, 2011) and Sutterlin et al (Sutterlin et al, 2018) identified and purified three L,D-transpeptidases, CD630_29630 (Ldt Cd1 ), CD630_27130 (Ldt Cd2 ) and CD630_30070 (Ldt Cd3 ), in C. difficile 630. Among them, Ldt Cd2 and Ldt Cd3 can catalyse the formation of 3 !…”

Section: Discussionmentioning

confidence: 99%

“…The putative N-terminal catalytic domain belongs to the Erfk (YkuD) superfamily (COG1376) with L,Dtranspeptidase activity, the C-terminal domain contains three tandem repeats of the cell wall binding motif CWB2 (pfam04122), and the Glucan-binding domain belongs to the COG5263 superfamily, which plays role of carbohydrate transport and metabolism. The similar domains of Cwp22 (CD630_27130) in C. difficile 630 were identified and characterized in vitro in previous work (Peltier et al, 2011;Sutterlin et al, 2018).…”

Section: Bioinformatic Identification and Analysis Of Putative Cell Wmentioning

confidence: 99%

“…The biochemical function of Cwp22 (CD630_27130) as an L, D-transpeptidase has been demonstrated in C. difficile 630 (Peltier et al, 2011;Sutterlin et al, 2018). Here, we identified the homologous protein (CDR20291_2601) from the epidemic strain C. difficile R20291 (referred hereafter as R20291) using a reverse vaccinology method and studied the role of this protein in vivo by phenotypically characterizing a strain with an insertional inactivation of the cwp22 gene (CDR20291_2601, referred hereafter as 2601 gene).…”

Section: Introductionmentioning

confidence: 99%

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Cwp22, a novel peptidoglycan cross‐linking enzyme, plays pleiotropic roles in Clostridioides difficile

Zhu

Bullock

2019

Environmental Microbiology

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Summary Clostridioides difficile is a Gram‐positive, spore‐forming, toxin‐producing anaerobe pathogen, and can induce nosocomial antibiotic‐associated intestinal disease. While production of toxin A (TcdA) and toxin B (TcdB) contribute to the main pathogenesis of C. difficile, adhesion and colonization of C. difficile in the host gut are prerequisites for disease onset. Previous cell wall proteins (CWPs) were identified that were implicated in C. difficile adhesion and colonization. In this study, we predicted and characterized Cwp22 (CDR20291_2601) from C. difficile R20291 to be involved in bacterial adhesion based on the Vaxign reverse vaccinology tool. The ClosTron‐generated cwp22 mutant showed decreased TcdA and TcdB production during early growth, and increased cell permeability and autolysis. Importantly, the cwp22 mutation impaired cellular adherence in vitro and decreased cytotoxicity and fitness over the parent strain in a mouse infection model. Furthermore, lactate dehydrogenase cytotoxicity assay, live‐dead cell staining and transmission electron microscopy confirmed the decreased cell viability of the cwp22 mutant. Thus, Cwp22 is involved in cell wall integrity and cell viability, which could affect most phenotypes of R20291. Our data suggest that Cwp22 is an attractive target for C. difficile infection therapeutics and prophylactics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Bioinformatic Identification and Analysis Of Putative Cell Wmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cwp22, a novel peptidoglycan cross‐linking enzyme, plays pleiotropic roles in Clostridioides difficile

Zhu

Bullock

2019

Environmental Microbiology

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Non‐Hydrolytic β‐Lactam Antibiotic Fragmentation by l,d‐Transpeptidases and Serine β‐Lactamase Cysteine Variants

et al. 2019

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Enzymes often use nucleophilic serine,t hreonine, and cysteine residues to achieve the same type of reaction;the underlying reasons for this are not understood. While bacterial d,d-transpeptidases (penicillin-binding proteins) employ an ucleophilic serine, l,d-transpeptidases use an ucleophilic cysteine.T he covalent complexes formed by l,d-transpeptidases with some b-lactam antibiotics undergo non-hydrolytic fragmentation. This is not usually observed for penicillinbinding proteins,o rf or the related serine b-lactamases. Replacement of the nucleophilic serine of serine b-lactamases with cysteine yields enzymes whichf ragment b-lactams via as imilar mechanism as the l,d-transpeptidases,i mplying the different reaction outcomes are principally due to the formation of thioester versus ester intermediates.The results highlight fundamental differences in the reactivity of nucleophilic serine and cysteine enzymes,a nd imply new possibilities for the inhibition of nucleophilic enzymes.Nature employs enzymes with nucleophilic serine,t hreonine,orcysteine residues to catalyze closely related reactions. Well-known examples of this are the serine and cysteine proteases,i nw hich these different nucleophilic residues are used to cleave peptide bonds.A na nalogous situation exists for the transpeptidase enzymes involved in bacterial peptidoglycan biosynthesis;the d,d-transpeptidases (or penicillinbinding proteins;P BPs) employ an ucleophilic serine, whereas the l,d-transpeptidases (Ldts) employ anucleophilic cysteine.T he reasons for the use of ap articular nucleophilic residue in ap articular enzyme context are not understood.

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Integration of biophysical and biological approaches to validate fragment-like compounds targeting l,d-transpeptidases from Mycobacterium tuberculosis

Andrés Libreros-Zúñiga,

Pavão e Pavão,

de Morais Barroso

et al. 2024

Bioorganic Chemistry

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Peptidoglycan Cross-Linking Activity of l , d -Transpeptidases from Clostridium difficile and Inactivation of These Enzymes by β-Lactams

Abstract: difficile-associated diseases. 52The structure of cell wall peptidoglycan is unusual in C. difficile since the majority

Cited by 27 publications

References 24 publications

Cwp22, a novel peptidoglycan cross‐linking enzyme, plays pleiotropic roles in Clostridioides difficile

Cwp22, a novel peptidoglycan cross‐linking enzyme, plays pleiotropic roles in Clostridioides difficile

Non‐Hydrolytic β‐Lactam Antibiotic Fragmentation by l,d‐Transpeptidases and Serine β‐Lactamase Cysteine Variants

Integration of biophysical and biological approaches to validate fragment-like compounds targeting l,d-transpeptidases from Mycobacterium tuberculosis

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