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Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli

The bacterial cell wall plays a crucial role in viability and is an important drug target. In Escherichia coli, the peptidoglycan crosslinking reaction to form the cell wall is primarily carried out by penicillin-binding proteins that catalyse D,D-transpeptidase activity. However, an alternate cross...

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Autores principales: Caveney, Nathanael A., Caballero, Guillermo, Voedts, Henri, Niciforovic, Ana, Worrall, Liam J., Vuckovic, Marija, Fonvielle, Matthieu, Hugonnet, Jean-Emmanuel, Arthur, Michel, Strynadka, Natalie C. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478713/
https://www.ncbi.nlm.nih.gov/pubmed/31015395
http://dx.doi.org/10.1038/s41467-019-09507-0
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author Caveney, Nathanael A.
Caballero, Guillermo
Voedts, Henri
Niciforovic, Ana
Worrall, Liam J.
Vuckovic, Marija
Fonvielle, Matthieu
Hugonnet, Jean-Emmanuel
Arthur, Michel
Strynadka, Natalie C. J.
author_facet Caveney, Nathanael A.
Caballero, Guillermo
Voedts, Henri
Niciforovic, Ana
Worrall, Liam J.
Vuckovic, Marija
Fonvielle, Matthieu
Hugonnet, Jean-Emmanuel
Arthur, Michel
Strynadka, Natalie C. J.
author_sort Caveney, Nathanael A.
collection PubMed
description The bacterial cell wall plays a crucial role in viability and is an important drug target. In Escherichia coli, the peptidoglycan crosslinking reaction to form the cell wall is primarily carried out by penicillin-binding proteins that catalyse D,D-transpeptidase activity. However, an alternate crosslinking mechanism involving the L,D-transpeptidase YcbB can lead to bypass of D,D-transpeptidation and beta-lactam resistance. Here, we show that the crystallographic structure of YcbB consists of a conserved L,D-transpeptidase catalytic domain decorated with a subdomain on the dynamic substrate capping loop, peptidoglycan-binding and large scaffolding domains. Meropenem acylation of YcbB gives insight into the mode of inhibition by carbapenems, the singular antibiotic class with significant activity against L,D-transpeptidases. We also report the structure of PBP5-meropenem to compare interactions mediating inhibition. Additionally, we probe the interaction network of this pathway and assay beta-lactam resistance in vivo. Our results provide structural insights into the mechanism of action and the inhibition of L,D-transpeptidation, and into YcbB-mediated antibiotic resistance.
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spelling pubmed-64787132019-04-25 Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli Caveney, Nathanael A. Caballero, Guillermo Voedts, Henri Niciforovic, Ana Worrall, Liam J. Vuckovic, Marija Fonvielle, Matthieu Hugonnet, Jean-Emmanuel Arthur, Michel Strynadka, Natalie C. J. Nat Commun Article The bacterial cell wall plays a crucial role in viability and is an important drug target. In Escherichia coli, the peptidoglycan crosslinking reaction to form the cell wall is primarily carried out by penicillin-binding proteins that catalyse D,D-transpeptidase activity. However, an alternate crosslinking mechanism involving the L,D-transpeptidase YcbB can lead to bypass of D,D-transpeptidation and beta-lactam resistance. Here, we show that the crystallographic structure of YcbB consists of a conserved L,D-transpeptidase catalytic domain decorated with a subdomain on the dynamic substrate capping loop, peptidoglycan-binding and large scaffolding domains. Meropenem acylation of YcbB gives insight into the mode of inhibition by carbapenems, the singular antibiotic class with significant activity against L,D-transpeptidases. We also report the structure of PBP5-meropenem to compare interactions mediating inhibition. Additionally, we probe the interaction network of this pathway and assay beta-lactam resistance in vivo. Our results provide structural insights into the mechanism of action and the inhibition of L,D-transpeptidation, and into YcbB-mediated antibiotic resistance. Nature Publishing Group UK 2019-04-23 /pmc/articles/PMC6478713/ /pubmed/31015395 http://dx.doi.org/10.1038/s41467-019-09507-0 Text en © Crown 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Caveney, Nathanael A.
Caballero, Guillermo
Voedts, Henri
Niciforovic, Ana
Worrall, Liam J.
Vuckovic, Marija
Fonvielle, Matthieu
Hugonnet, Jean-Emmanuel
Arthur, Michel
Strynadka, Natalie C. J.
Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli
title Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli
title_full Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli
title_fullStr Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli
title_full_unstemmed Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli
title_short Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli
title_sort structural insight into ycbb-mediated beta-lactam resistance in escherichia coli
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478713/
https://www.ncbi.nlm.nih.gov/pubmed/31015395
http://dx.doi.org/10.1038/s41467-019-09507-0
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