文献类型：期刊文献

英文题名：Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-β-lactamases

作者：Hu, Liqiang[1];Yang, Huixin[1,2];Yu, Tao[1];Chen, Fangfang[1];Liu, Runqiu[1];Xue, Shuyuan[1];Zhang, Shuangzhan[1];Mao, Wuyu[1];Ji, Changge[3];Wang, Hao[3];Xie, Hexin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Frontiers Sci Ctr Materiobiol & Dynam Chem, State Key Lab Bioreactor Engn,Sch Pharm, Shanghai 200237, Peoples R China;[2]Quanzhou Matern & Childrens Hosp, Clin Lab, 700 Fengze St, Quanzhou 362000, Fujian, Peoples R China;[3]East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China

年份：2022

卷号：232

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000803062900009)】；

基金：We are grateful for financial support from the NSFC-BRICS (81861148020, HX), the Fundamental Research Funds for the Central Universities (HX), the Research Program of State Key Laboratory of Bioreactor Engineering (HX), Quanzhou Municipal Science and Technology Plan Project (2020C016R, HY), and National Key Research and Development Plan (2016YFA0501700, CJ).

语种：英文

外文关键词：Antibiotic resistance; beta-lactamase; Inhibitor; New Delhi metallo-beta-lactamase

摘要：Antibiotic resistance caused by beta-lactamases, particularly metallo-beta-lactamases, has been a major threat to public health globally. New Delhi metallo-beta-lactamase-1 (NDM-1) represents one of the most important metallo-beta-lactamases; the production of NDM-1 in bacterial pathogen significantly reduces the efficacy of beta-lactam antibiotics, including life-saving carbapenems. Herein, we have demonstrated stereochemically altered cephalosporins as potent inhibitors against NDM-1, as well as mutants of NDM. The structure and activity relationship (SAR) study on over twenty cephalosporin analogues discloses the stereochemistry and the substituents on 7-position and 30-position of cephalosporin are critical to suppress the activity of NDM-1 and the optimal compound 1u exhibited an IC50 of 0.13 mM. Furthermore, a crystal complex of NDM-1 and 1u has been obtained, suggesting this cephalosporin derivative inhibits enzyme activity by the formation of a relatively stable hydrolytic product-NDM-1 intermediate. The discovery in this study may pave the way to turn cephalosporin, a natural substrate of beta-lactamase, into an effective NDM-1 inhibitor to combat antibiotic resistance. (c) 2022 Elsevier Masson SAS. All rights reserved.