Factors essential for L,D-transpeptidase-mediated peptidoglycan cross-linking and β-lactam resistance in Escherichia coli
Jean-Emmanuel Hugonnet,
Dominique Mengin-Lecreulx,
Alejandro Monton,
Tanneke den Blaauwen,
Etienne Carbonnelle,
Carole Veckerlé,
Yves, V. Brun,
Michael van Nieuwenhze,
Christiane Bouchier,
Kuyek Tu,
Louis B Rice,
Michel Arthur
Affiliations
Jean-Emmanuel Hugonnet
INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Universités, UPMC Université Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
Dominique Mengin-Lecreulx
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France
Alejandro Monton
Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
Tanneke den Blaauwen
Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
Etienne Carbonnelle
INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Universités, UPMC Université Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
Carole Veckerlé
INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Universités, UPMC Université Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
Yves, V. Brun
Indiana University, Indiana, United States
Michael van Nieuwenhze
Indiana University, Indiana, United States
Christiane Bouchier
Institut Pasteur, Paris, France
Kuyek Tu
INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Universités, UPMC Université Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
Louis B Rice
Rhode Island Hospital, Brown University, Providence, United States
INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Universités, UPMC Université Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
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.
