Synthesis of Avibactam Derivatives and Activity on β-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Chemistry - A European Journal Année : 2018

Synthesis of Avibactam Derivatives and Activity on β-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria

Flavie Bouchet
  • Fonction : Auteur
Eva Le Run
  • Fonction : Auteur

Résumé

There is a renewed interest for β-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their β-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen-Sharpless cycloaddition reaction is reported. The amoxicillin-DBO combinations were active, indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 μg mL-1 for both species). Mechanistically, β-lactamase inhibition was not sufficient to account for the potentiation of amoxicillin by DBOs. Thus, the latter compounds were investigated as inhibitors of l,d-transpeptidases (Ldts), which are the main peptidoglycan polymerases in mycobacteria. The DBOs acted as slow-binding inhibitors of Ldts by S-carbamoylation indicating that optimization of DBOs for Ldt inhibition is an attractive strategy to obtain drugs selectively active on mycobacteria.
Fichier non déposé

Dates et versions

hal-02177911 , version 1 (09-07-2019)

Identifiants

Citer

Zainab Edoo, Laura Iannazzo, Fabrice Compain, Inès Li de La Sierra Gallay, Herman Van Tilbeurgh, et al.. Synthesis of Avibactam Derivatives and Activity on β-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria. Chemistry - A European Journal, 2018, 24 (32), pp.8081--8086. ⟨10.1002/chem.201800923⟩. ⟨hal-02177911⟩
95 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More