6FJ1

Structure of the Ldtfm-avibactam carbamoyl enzyme

6FJ1 の概要

• エントリーDOI: 10.2210/pdb6fj1/pdb
• 分子名称: L,D-TRANSPEPTIDASE, 3,6,9,12,15-PENTAOXAHEPTADECANE, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, ... (6 entities in total)
• 機能のキーワード: l, d-transpeptidation, peptidoglycan, antibiotic resistance, avibactam, nxl104, antibiotic, hydrolase
• 由来する生物種: Enterococcus faecium (Streptococcus faecium)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 88754.71

構造登録者

Li de la Sierra Gallay, I.,Iannazzo, L.,Compain, F.,Fonvielle, M.,van Tilbeurgh, H.,Edoo, Z.,Arthur, M.,Etheve-Quelquejeu, M.,Hugonnet, J. (登録日: 2018-01-19, 公開日: 2019-01-30, 最終更新日: 2024-10-23)

主引用文献

Edoo, Z.,Iannazzo, L.,Compain, F.,Li de la Sierra Gallay, I.,van Tilbeurgh, H.,Fonvielle, M.,Bouchet, F.,Le Run, E.,Mainardi, J.L.,Arthur, M.,Etheve-Quelquejeu, M.,Hugonnet, J.E.
Synthesis of Avibactam Derivatives and Activity on beta-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria.
Chemistry, 24:8081-8086, 2018

PubMed Abstract: 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 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.

PubMed: 29601108
DOI: 10.1002/chem.201800923

実験手法

X-RAY DIFFRACTION (2.69 Å)