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A Novel Peptidoglycan Cross-linking Enzyme for a β-Lactam-resistant Transpeptidation Pathway

2005; Elsevier BV; Volume: 280; Issue: 46 Linguagem: Inglês

10.1074/jbc.m507384200

1083-351X

Jean‐Luc Mainardi, Martine Fourgeaud, Jean‐Emmanuel Hugonnet, Lionel Dubost, Jean‐Paul Brouard, Jamal Ouazzani, Louis B. Rice, Laurent Gutmann, Michel Arthur,

Antimicrobial Resistance in Staphylococcus

The beta-lactam antibiotics remain the most commonly used to treat severe infections. Because of structural similarity between the beta-lactam ring and the d-alanyl(4)-d-alanine(5) extremity of bacterial cell wall precursors, the drugs act as suicide substrates of the dd-transpeptidases that catalyze the last cross-linking step of cell wall assembly. Here, we show that this mechanism of action can be defeated by a novel type of transpeptidase identified for the first time by reverse genetics in abeta-lactam-resistant mutant of Enterococcus faecium. The enzyme, Ldt(fm), catalyzes in vitro the cross-linking of peptidoglycan subunits in a beta-lactam-insensitive ld-transpeptidation reaction. The specificity of Ldt(fm) for the l-lysyl(3)-d-alanine(4) peptide bond of tetrapeptide donors accounts for resistance because the substrate does not mimic beta-lactams in contrast to d-alanyl(4)-d-alanine(5) in the pentapeptide donors required for dd-transpeptidation. Ldt(fm) homologues are encountered sporadically among taxonomically distant bacteria, indicating that ld-transpeptidase-mediated resistance may emerge in various pathogens.