title: Routes of Synthesis of Carbapenems for Optimizing Both the Inactivation of L,D-Transpeptidase LdtMt1 of Mycobacterium tuberculosis and the Stability toward Hydrolysis by β-Lactamase BlaC.
abstract: Combinations of β-lactams of the carbapenem class, such as meropenem, with clavulanate, a β-lactamase inhibitor, are being evaluated for the treatment of drug-resistant tuberculosis. However, carbapenems approved for human use have never been optimized for inactivation of the unusual β-lactam targets of Mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum β-lactamase BlaC. Here, we report three routes of synthesis for modification of the two side chains carried by the β-lactam and the five-membered rings of the carbapenem core. In particular, we show that the azide-alkyne Huisgen cycloaddition reaction catalyzed by copper(I) is fully compatible with the highly unstable β-lactam ring of carbapenems and that the triazole ring generated by this reaction is well tolerated for inactivation of the L,D-transpeptidase LdtMt1 target. Several of our new carbapenems are superior to meropenem both with respect to the efficiency of in vitro inactivation of LdtMt1 and reduced hydrolysis by BlaC.
authors.affiliation: Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, team CBNIT, Université Paris Descartes , CNRS UMR 8601, Paris F-75006, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Iannazzo
authors.forename: Daria
authors.initials: D
authors.lastname: Soroka
authors.forename: Sébastien
authors.initials: S
authors.lastname: Triboulet
authors.forename: Matthieu
authors.initials: M
authors.lastname: Fonvielle
authors.forename: Fabrice
authors.initials: F
authors.lastname: Compain
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service de Réanimation Médicale, Hôpital Saint-Antoine , Paris F-75012, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dubée
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service de Microbiologie, Hôpital Européen Georges Pompidou , Paris F-75015, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Mainardi
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Hugonnet
authors.affiliation: Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, team CBNIT, Université Paris Descartes , CNRS UMR 8601, Paris F-75006, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Braud
authors.forename: Michel
authors.initials: M
authors.lastname: Arthur
authors.affiliation: Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, team CBNIT, Université Paris Descartes , CNRS UMR 8601, Paris F-75006, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Etheve-Quelquejeu
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015780:Carbapenems / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D015780:Carbapenems; D065093:beta-Lactamase Inhibitors; D010458:Peptidyl Transferases; D001618:beta-Lactamases