文献类型：期刊文献

中文题名：Strategic design of lysine-targeted irreversible covalent NDM-1 inhibitors

作者：Youzhen Ma[1];Yongxi Liang[1];Menglu Guo[1];Delin Min[1];Lulu Zheng[3];Yun Tang[3];Xun Sun[1,2]

机构：[1]Department of Natural Medicine,School of Pharmacy,Fudan University,Shanghai 201203,China;[2]The Institutes of Integrative Medicine of Fudan University,Shanghai 200040,China;[3]Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China

年份：2023

卷号：34

期号：7

起止页码：146

中文期刊名：Chinese Chemical Letters

外文期刊名：中国化学快报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2023_2024】；PubMed;

基金：funded by the National Natural Science Foundation of China (No. 82073688 to X. Sun and No. 82103971 to Y. Liang);Science and Technology Commission of Shanghai Municipality (No. 21S11907300 to X. Sun);Shanghai Science and Technology Development Fund from Central Leading Local Government (No. YDZX20223100001004 to X. Sun)。

语种：英文

中文关键词：Covalent inhibitors;Lysine;Irreversible;Metallo-β-lactamase;Antimicrobial activity

摘要：New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relatively weak due to the shallow active pocket of NDM-1. Alternatively, irreversible covalent inhibitors can prevent their dissociation from the target, leading to permanent inactivation of the protein.Herein, we report a series of irreversible covalent inhibitors of NDM-1 targeting the conserved Lys211 in the active pocket. Several methods, including mass spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fluorescent labeling, and coumarin probe were used to demonstrate that pentafluorophenyl ester formed a covalent bond with Lys211. Moreover, our target inhibitor, in combination with meropenem, achieved an antibacterial effect on drug-resistant bacteria, along with an excellent safety profile. Our new strategy in designing lysine-targeted irreversible covalent NDM-1 inhibitors provides a potential option for the clinical treatment of Gram-negative bacteria.