Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-beta-lactamase-1
Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-beta-lactamase-1
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H2dedpa 衍生物作为新德里 Metallo-β-lactamase-1 有效抑制剂的系统研究
DOI：
10.1016/j.bioorg.2020.103965
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发表时间：
2020
影响因子：
5.1
通讯作者：
Zhang En
中科院分区：
文献类型：
--
作者：
Cui De-Yun;Yang Yi;Bai Meng-Meng;Han Jiang-Xue;Wang Cong-Cong;Kong Hong-Tao;Shen Bo-Yuan;Yan Da-Chao;Xiao Chun-Ling;Liu Yi-Shuang;Zhang En
新德里金属-β-内酰胺酶-1 （NDM-1）是一种锌（II）依赖性酶，可催化水解包括碳青霉烯类在内的几乎所有β-内酰胺类抗生素，导致细菌对抗生素产生耐药性，威胁全球公共卫生。基于我们发现H2dedpa是一种高效的NDM-1抑制剂，我们系统地制备了一系列H2dedpa衍生物。这些化合物对NDM-1具有显著的抑制活性，ic50值为0.06 ~ 0.94 μM。在体外实验中，化合物6和6能恢复美罗培南对肺炎克雷伯菌、大肠杆菌和具有NDM或IMP的奇异变形杆菌的活性，特别是对ste的活性。使用这两种化合物可使NDM-4的大肠杆菌产量提高5333倍。基于时间杀伤细胞的测定显示，99.9%的p。当美罗培南与化合物6kor6n联合治疗时，奇迹被杀死。此外，化合物6和6n是非溶血性的（HC50 ~ 1280 μg/mL），对哺乳动物（HeLa）细胞具有低毒性。机制研究表明，化合物6和6n通过螯合酶的Zn2+离子抑制NDM-1。
New Delhi Metallo-β-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all β-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50values 0.06–0.94 μM.In vitro, compounds6kand6ncould restore the activity of meropenem againstKlebsiella pneumoniae,Escherichia coliandProteus mirabilispossessing either NDM or IMP. In particular, the activity of meropenem againstE. coliproducing NDM-4 could be improved up to 5333 times when these two compounds were used. Time–kill cell-based assays showed that 99.9% ofP. mirabiliswere killed when treated with meropenem in combination with compound6kor6n. Furthermore, compounds6kand6nwere nonhemolytic (HC50> 1280 μg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds6kand6ninhibit NDM-1 by chelating the Zn2+ion of the enzyme.