RESEARCH ARTICLE Factors essential for L,D-transpeptidase- mediated peptidoglycan cross-linking and b-lactam resistance in Escherichia coli Jean-Emmanuel Hugonnet1,2,3, Dominique Mengin-Lecreulx4, Alejandro Monton5, Tanneke den Blaauwen5, Etienne Carbonnelle1,2,3, Carole Veckerle´ 1,2,3, Yves, V. Brun6, Michael van Nieuwenhze6, Christiane Bouchier7, Kuyek Tu1,2,3, Louis B Rice8, Michel Arthur1,2,3* 1INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; 2Sorbonne Universite´s, UPMC Universite´ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; 3Universite´ Paris Descartes, Sorbonne Paris Cite´, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; 4Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Universite´ Paris-Sud, Universite´ Paris-Saclay, Gif-sur-Yvette, France; 5Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands; 6Indiana University, Indiana, United States; 7Institut Pasteur, Paris, France; 8Rhode Island Hospital, Brown University, Providence, United States Abstract The target of b-lactam antibiotics is the D,D-transpeptidase activity of penicillin- binding proteins (PBPs) for synthesis of 4fi3 cross-links in the peptidoglycan of bacterial cell walls. Unusual 3fi3 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 *For correspondence: michel. synthesis of the (p)ppGpp alarmone by RelA lead to full bypass of the D,D-transpeptidase activity
[email protected] of PBPs and to broad-spectrum b-lactam resistance.