化学
抗菌剂
抗生素
美罗培南
新德里
活动站点
抗生素耐药性
组合化学
酶
微生物学
立体化学
生物化学
生物
医学
有机化学
病理
大都市区
作者
Jérémy Caburet,Federica Verdirosa,Marino Moretti,Brayan Roulier,Giorgia Simoncelli,Romain Haudecoeur,Somayeh Ghazi,Hélène Jamet,J.D. Docquier,Benjamin Boucherle,Marine Peuchmaur
标识
DOI:10.1016/j.bmc.2023.117559
摘要
Bacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-β-lactamases (MBLs) able to hydrolytically inactivate β-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-β-lactamase-1 (NDM-1) is still considered as one of the most relevant targets for inhibitor development. Following a fragment-based strategy to find new NDM-1 inhibitors, we identified aurone as a promising scaffold. A series of 60 derivatives were then evaluated and two of them were identified as promising inhibitors with Ki values as low as 1.7 and 2.5 µM. Moreover, these two most active compounds were able to potentiate meropenem in in vitro antimicrobial susceptibility assays. The molecular modelling provided insights about their likely interactions with the active site of NDM-1, thus enabling further improvement in the structure of this new inhibitor family.
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