Structure of Enterococcus faeciuml,d-transpeptidase acylated by ertapenem provides insight into the inactivation mechanism.
Lauriane Lecoq,Vincent Dubée,Vincent Dubée,Vincent Dubée,Sébastien Triboulet,Sébastien Triboulet,Sébastien Triboulet,Catherine M. Bougault,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Michel Arthur,Michel Arthur,Michel Arthur,Jean-Pierre Simorre +14 more
TLDR
The first structure of a carbapenem-acylated l,d-transpeptidase is presented, E. faecium Ldtfm acylated by ertapenems, which revealed key contacts between the carbapanem core and residues of the catalytic cavity of the enzyme.Abstract:
The maintenance of bacterial cell shape and integrity is largely attributed to peptidoglycan, a biopolymer highly cross-linked through d,d-transpeptidation. Peptidoglycan cross-linking is catalyzed by penicillin-binding proteins (PBPs) that are the essential target of β-lactam antibiotics. PBPs are functionally replaced by l,d-transpeptidases (Ldts) in ampicillin-resistant mutants of Enterococcus faecium and in wild-type Mycobacterium tuberculosis. Ldts are inhibited in vivo by a single class of β-lactams, the carbapenems, which act as a suicide substrate. We present here the first structure of a carbapenem-acylated l,d-transpeptidase, E. faecium Ldtfm acylated by ertapenem, which revealed key contacts between the carbapenem core and residues of the catalytic cavity of the enzyme. Significant reorganization of the antibiotic conformation occurs upon enzyme acylation. These results, together with the analysis of protein-to-carbapenem proton transfers, provide new insights into the mechanism of Ldt acylation by carbapenems.read more
Citations
More filters
Journal ArticleDOI
Resistance to antibiotics targeted to the bacterial cell wall.
TL;DR: This review provides an overview of resistance mechanisms developed toward antibiotics that target bacterial cell wall precursors and its biosynthetic machinery and strategies toward the development of novel inhibitors that could overcome resistance.
Journal ArticleDOI
Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials.
Eric Sauvage,Mohammed Terrak +1 more
TL;DR: A general background on the GTs and TPs/PBPs, a survey of recent issues of bacterial resistance and a review of recent works describing new inhibitors of these enzymes are presented.
Journal ArticleDOI
Kinetic features of L,D-transpeptidase inactivation critical for β-lactam antibacterial activity.
Sébastien Triboulet,Sébastien Triboulet,Sébastien Triboulet,Vincent Dubée,Vincent Dubée,Vincent Dubée,Lauriane Lecoq,Lauriane Lecoq,Catherine M. Bougault,Catherine M. Bougault,Jean-Luc Mainardi,Louis B. Rice,Mélanie Etheve-Quelquejeu,Mélanie Etheve-Quelquejeu,Laurent Gutmann,Arul Marie,Lionel Dubost,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Jean-Pierre Simorre,Jean-Pierre Simorre,Michel Arthur,Michel Arthur,Michel Arthur +24 more
TL;DR: It is shown that imipenem, ceftriaxone, and ampicillin acylate Ldtfm by formation of a thioester bond between the active-site cysteine and the β-lactam-ring carbonyl, which is critical for rapid L,D-transpeptidase inactivation and antibacterial activity.
Journal ArticleDOI
Structures of free and inhibited forms of the L,D-transpeptidase LdtMt1 from Mycobacterium tuberculosis.
TL;DR: By providing the key interactions in the binding of carbapenem to LdtMt1, this work will facilitate structure-guided discovery of L,D-transpeptidase inhibitors as novel antitubercular agents against drug-resistant M. tuberculosis.
Journal ArticleDOI
β-Lactam Resistance Mechanisms: Gram-Positive Bacteria and Mycobacterium tuberculosis.
Jed F. Fisher,Shahriar Mobashery +1 more
TL;DR: The emergence of strains of this bacterium resistant to virtually all other antibiotics has compelled the evaluation of newer β-lactam combinations as possible contributors to the multidrug chemotherapy required to control tubercular infection.
References
More filters
Journal ArticleDOI
LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions
TL;DR: The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities.
Journal ArticleDOI
PRODRG: a tool for high-throughput crystallography of protein–ligand complexes
TL;DR: The small-molecule topology generator PRODRG is described, which takes input from existing coordinates or various two-dimensional formats and automatically generates coordinates and molecular topologies suitable for X-ray refinement of protein-ligand complexes.
Journal ArticleDOI
TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts.
TL;DR: Extension of the original 20-protein database to 200 proteins increased the fraction of residues for which backbone angles could be predicted from 65 to 74%, while reducing the error rate from 3 to 2.5%, and addition of a two-layer neural network filter to the database fragment selection process forms the basis for a new program, TALOS+, which further enhances the prediction rate to 88.5%.
Journal ArticleDOI
Version 1.2 of the Crystallography and NMR system
TL;DR: An improved model for the treatment of disordered solvent for crystallographic refinement that employs a combined grid search and least-squares optimization of the bulk solvent model parameters is included, resulting in lower R values.
Journal ArticleDOI
Carbapenems: Past, Present, and Future
Krisztina M. Papp-Wallace,Andrea Endimiani,Andrea Endimiani,Andrea Endimiani,Magdalena A. Taracila,Robert A. Bonomo +5 more
TL;DR: The current “state of the art” of carbapenem antibiotics and their role in the antimicrobial armamentarium are summarized and the medicinal chemist is urged to continue development of these versatile and potent compounds.
Related Papers (5)
Unexpected Inhibition of Peptidoglycan LD-Transpeptidase from Enterococcus faecium by the β-Lactam Imipenem *
Jean-Luc Mainardi,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Filippo Rusconi,Filippo Rusconi,Martine Fourgeaud,Martine Fourgeaud,Martine Fourgeaud,Lionel Dubost,Angèle Nguekam Moumi,Angèle Nguekam Moumi,Angèle Nguekam Moumi,Vanessa Delfosse,Vanessa Delfosse,Vanessa Delfosse,Claudine Mayer,Claudine Mayer,Claudine Mayer,Laurent Gutmann,Louis B. Rice,Michel Arthur,Michel Arthur,Michel Arthur +23 more
Inactivation of Mycobacterium tuberculosis l,d-Transpeptidase LdtMt1 by Carbapenems and Cephalosporins
Vincent Dubée,Vincent Dubée,Vincent Dubée,Sébastien Triboulet,Sébastien Triboulet,Sébastien Triboulet,Jean-Luc Mainardi,Mélanie Etheve-Quelquejeu,Laurent Gutmann,Arul Marie,Lionel Dubost,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Jean-Emmanuel Hugonnet,Michel Arthur,Michel Arthur,Michel Arthur +16 more