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Factors essential for L,D-transpeptidase-mediated peptidoglycan cross-linking and β-lactam resistance in Escherichia coli

2016; eLife Sciences Publications Ltd; Volume: 5; Linguagem: Inglês

10.7554/elife.19469

2050-084X

Jean‐Emmanuel Hugonnet, Dominique Mengin‐Lecreulx, Alejandro Monton, Tanneke den Blaauwen, Étienne Carbonnelle, Carole Veckerlé, Yves V. Brun, Michael van Nieuwenhze, Christiane Bouchier, Kuyek Tu, Louis B. Rice, Michel Arthur,

Enzyme Structure and Function

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.