A novel peptidoglycan cross-linking enzyme for a beta-lactam-resistant transpeptidation pathway |
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Authors: | Mainardi Jean-Luc Fourgeaud Martine Hugonnet Jean-Emmanuel Dubost Lionel Brouard Jean-Paul Ouazzani Jamal Rice Louis B Gutmann Laurent Arthur Michel |
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Institution: | INSERM, U655-Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie, Paris, France. jlmainar@bhdc.jussieu.fr |
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Abstract: | 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. |
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