Factors essential for L,D-transpeptidase-mediated peptidoglycan cross-linking and β-lactam resistance in Escherichia coli
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, France
- Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, France
- University of Amsterdam, Netherlands
- Indiana University, United States
- Institut Pasteur, France
- Brown University, United States
Abstract
The target of β-lactam antibiotics is the D,D-transpeptidase activity of penicillin-binding proteins (PBPs) for synthesis of 4→3 cross-links in the peptidoglycan of bacterial cell walls. Unusual 3→3 cross-links formed by L,D-transpeptidases were first detected in Escherichia coli more than four decades ago, however no phenotype has previously been associated with their synthesis. Here we show that production of the L,D-transpeptidase YcbB in combination with elevated synthesis of the (p)ppGpp alarmone by RelA lead to full bypass of the D,D-transpeptidase activity of PBPs and to broad-spectrum β-lactam resistance. Production of YcbB was therefore sufficient to switch the role of (p)ppGpp from antibiotic tolerance to high-level β-lactam resistance. This observation identifies a new mode of peptidoglycan polymerization in E. coli that relies on an unexpectedly small number of enzyme activities comprising the glycosyltransferase activity of class A PBP1b and the D,D-carboxypeptidase activity of DacA in addition to the L,D-transpeptidase activity of YcbB.
Data availability
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Raw genomic sequences of mecillinam and resistant mutants of E. coliAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
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Funding
National Institute of Allergy and Infectious Diseases (RO1 307 AI046626)
- Louis B Rice
- Michel Arthur
Joint Program Initiative on Antimicrobial Research (ZonMW project 60-60900-98-207)
- Alejandro Monton
Joint Program Initiative on Antimicrobial Research (NAPCLI)
- Jean-Emmanuel Hugonnet
- Alejandro Monton
- Tanneke den Blaauwen
- Michel Arthur
National Institutes of Health (GM113172)
- Michael van Nieuwenhze
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Further reading
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