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J. Biol. Chem., Vol. 280, Issue 46, 38146-38152, November 18, 2005

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

Jean-Luc Mainardi1, Martine Fourgeaud, Jean-Emmanuel Hugonnet, Lionel Dubost¶, Jean-Paul Brouard¶, Jamal Ouazzani||, Louis B. Rice**, Laurent Gutmann, and Michel Arthur

From the INSERM, U655-Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Pierre et Marie Curie (UPMC Paris 6), Faculté deMédecine, Université Paris-Descartes, and Centre de Recherches Biomédicales des Cordeliers, 15 rue de l'Ecole de Médecine, 75270 Paris Cedex 06, France, Faculté deMédecine, Université Paris-Descartes, AP-HP Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France, ^¶Plateforme de Spectrométrie de Masse et de Protéomique du Muséum, Département Recherche Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, USM0502-CNRS UMR8041, 75005 Paris, France, ^||Laboratoire de Microbiologie Appliquée, Institut de Chimie des Substances Naturelles, CNRS, 91190 Gif-sur-Yvette, France, and ^**Medical and Research Services, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106

The -lactam antibiotics remain the most commonly used to treat severe infections. Because of structural similarity between the -lactam ring and the D-alanyl⁴-D-alanine⁵ 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 a-lactam-resistant mutant of Enterococcus faecium. The enzyme, Ldt_fm, catalyzes in vitro the cross-linking of peptidoglycan subunits in a -lactam-insensitive LD-transpeptidation reaction. The specificity of Ldt_fm for the L-lysyl³-D-alanine⁴ peptide bond of tetrapeptide donors accounts for resistance because the substrate does not mimic -lactams in contrast to D-alanyl⁴-D-alanine⁵ 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.

Received for publication, July 7, 2005 , and in revised form, September 1, 2005.

^* This work was supported by the European Community (Combating Resistance to Antibiotics, contract Life Science Health Medicine Contract-2003-503335, 6th Programme Cadre de Recherche et de Développement Technologique) and by the NIAID, National Institutes of Health Grant R01 AI45626. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 33-1-42-34-68-62; Fax: 33-1-43-25-68-12; E-mail: jlmainar{at}bhdc.jussieu.fr.

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