Clostridioides difficile canonical L,D-transpeptidases catalyze a novel type of peptidoglycan cross-links and are not required for beta-lactam resistance
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
Clostridioides difficile is the leading cause of antibiotic-associated diarrhea worldwide with significant morbidity and mortality. This organism is naturally resistant to several beta-lactam antibiotics that inhibit the polymerization of peptidoglycan, an essential component of the bacteria cell envelope. Previous work has revealed that C. difficile peptidoglycan has an unusual composition. It mostly contains 3-3 cross-links, catalyzed by enzymes called L,D-transpeptidases (Ldts) that are poorly inhibited by beta-lactams. It was therefore hypothesized that peptidoglycan polymerization by these enzymes could underpin antibiotic resistance. Here, we investigated the catalytic activity of the three canonical Ldts encoded by C. difficile (LdtCd1, LdtCd2, and LdtCd3) in vitro and explored their contribution to growth and antibiotic resistance. We show that two of these enzymes catalyze the formation of novel types of peptidoglycan cross-links using meso-diaminopimelic acid both as a donor and an acceptor, also observed in peptidoglycan sacculi. We demonstrate that the simultaneous deletion of these three genes only has a minor impact on both peptidoglycan structure and resistance to beta-lactams. This unexpected result therefore implies that the formation of 3-3 peptidoglycan cross-links in C. difficile is catalyzed by as yet unidentified noncanonical Ldt enzymes.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:300 |
|---|---|
| Enthalten in: |
The Journal of biological chemistry - 300(2024), 1 vom: 01. Jan., Seite 105529 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Galley, Nicola F [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antibiotics |
|---|
| Anmerkungen: |
Date Completed 09.02.2024 Date Revised 13.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jbc.2023.105529 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365347809 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365347809 | ||
| 003 | DE-627 | ||
| 005 | 20240313233847.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jbc.2023.105529 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1326.xml |
| 035 | |a (DE-627)NLM365347809 | ||
| 035 | |a (NLM)38043796 | ||
| 035 | |a (PII)S0021-9258(23)02557-7 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Galley, Nicola F |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Clostridioides difficile canonical L,D-transpeptidases catalyze a novel type of peptidoglycan cross-links and are not required for beta-lactam resistance |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.02.2024 | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Clostridioides difficile is the leading cause of antibiotic-associated diarrhea worldwide with significant morbidity and mortality. This organism is naturally resistant to several beta-lactam antibiotics that inhibit the polymerization of peptidoglycan, an essential component of the bacteria cell envelope. Previous work has revealed that C. difficile peptidoglycan has an unusual composition. It mostly contains 3-3 cross-links, catalyzed by enzymes called L,D-transpeptidases (Ldts) that are poorly inhibited by beta-lactams. It was therefore hypothesized that peptidoglycan polymerization by these enzymes could underpin antibiotic resistance. Here, we investigated the catalytic activity of the three canonical Ldts encoded by C. difficile (LdtCd1, LdtCd2, and LdtCd3) in vitro and explored their contribution to growth and antibiotic resistance. We show that two of these enzymes catalyze the formation of novel types of peptidoglycan cross-links using meso-diaminopimelic acid both as a donor and an acceptor, also observed in peptidoglycan sacculi. We demonstrate that the simultaneous deletion of these three genes only has a minor impact on both peptidoglycan structure and resistance to beta-lactams. This unexpected result therefore implies that the formation of 3-3 peptidoglycan cross-links in C. difficile is catalyzed by as yet unidentified noncanonical Ldt enzymes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Clostridioides difficile | |
| 650 | 4 | |a L,D-transpeptidase | |
| 650 | 4 | |a antibiotics | |
| 650 | 4 | |a bacterial cell envelope | |
| 650 | 4 | |a beta-lactams | |
| 650 | 4 | |a cross-link | |
| 650 | 4 | |a peptidoglycan | |
| 650 | 7 | |a Bacterial Proteins |2 NLM | |
| 650 | 7 | |a beta-Lactams |2 NLM | |
| 650 | 7 | |a Peptidoglycan |2 NLM | |
| 650 | 7 | |a Peptidyl Transferases |2 NLM | |
| 650 | 7 | |a EC 2.3.2.12 |2 NLM | |
| 700 | 1 | |a Greetham, Darren |e verfasserin |4 aut | |
| 700 | 1 | |a Alamán-Zárate, Marcel G |e verfasserin |4 aut | |
| 700 | 1 | |a Williamson, Mike P |e verfasserin |4 aut | |
| 700 | 1 | |a Evans, Caroline A |e verfasserin |4 aut | |
| 700 | 1 | |a Spittal, William D |e verfasserin |4 aut | |
| 700 | 1 | |a Buddle, Jessica E |e verfasserin |4 aut | |
| 700 | 1 | |a Freeman, Jane |e verfasserin |4 aut | |
| 700 | 1 | |a Davis, Georgina L |e verfasserin |4 aut | |
| 700 | 1 | |a Dickman, Mark J |e verfasserin |4 aut | |
| 700 | 1 | |a Wilcox, Mark H |e verfasserin |4 aut | |
| 700 | 1 | |a Lovering, Andrew L |e verfasserin |4 aut | |
| 700 | 1 | |a Fagan, Robert P |e verfasserin |4 aut | |
| 700 | 1 | |a Mesnage, Stéphane |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of biological chemistry |d 1945 |g 300(2024), 1 vom: 01. Jan., Seite 105529 |w (DE-627)NLM000004995 |x 1083-351X |7 nnns |
| 773 | 1 | 8 | |g volume:300 |g year:2024 |g number:1 |g day:01 |g month:01 |g pages:105529 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jbc.2023.105529 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 300 |j 2024 |e 1 |b 01 |c 01 |h 105529 | ||