Discovery of a Novel Natural Allosteric Inhibitor That Targets NDM-1 Against Escherichia coli.
Discovery of a Novel Natural Allosteric Inhibitor That Targets NDM-1 Against Escherichia coli.
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发现一种针对 NDM-1 的新型天然变构抑制剂来对抗大肠杆菌
DOI：
10.3389/fphar.2020.581001
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发表时间：
2020
影响因子：
5.6
通讯作者：
Niu X
中科院分区：
文献类型：
--
作者：
Yang Y;Guo Y;Zhou Y;Gao Y;Wang X;Wang J;Niu X
目前，作为细菌对β-内酰胺类抗生素耐药机制之一的新德里金属β-内酰胺酶-1（NDM-1）对碳青霉烯类和头孢菌素类的耐药，对人类健康构成威胁。在这项工作中，基于虚拟配体筛选方法，我们发现鼠尾草酸1（CA），一种天然化合物，对NDM-1表现出显着的抑制作用（IC 50 = 27.07 μM）。虽然鼠尾草酸没有显示出直接的抗菌活性，但鼠尾草酸和美罗培南的组合在美罗培南的杀菌作用丧失后仍显示出杀菌活性。实验结果表明，鼠尾草酸能增强美罗培南对大肠杆菌ZC-YN 3的抗菌活性。为探讨鼠尾草酸对NDM-1的抑制作用机制，对NDM-1-CA复合体系进行了分子动力学模拟和结合能计算。值得注意的是，从分子模拟获得的复合物的3D结构表明鼠尾草酸与NDM-1的结合区域不位于蛋白质的活性区域。由于与鼠尾草酸的变构口袋结合，观察到NDM-1的活性区构象已被改变。NDM-1-CA复合物与活性中心的距离大于游离蛋白，导致活性丧失。然后，突变实验表明鼠尾草酸对突变蛋白的抑制活性低于野生型蛋白。荧光实验验证了上述报道的结果。因此，我们的数据表明鼠尾草酸是一种潜在的NDM-1抑制剂，是一种有前途的药物，用于治疗NDM-1产生的病原体。
At present, the resistance of New Delhi metallo-β-lactamase-1 (NDM-1) to carbapenems and cephalosporins, one of the mechanisms of bacterial resistance against β-lactam antibiotics, poses a threat to human health. In this work, based on the virtual ligand screen method, we found that carnosic acid1 (CA), a natural compound, exhibited a significant inhibitory effect against NDM-1 (IC50 = 27.07 μM). Although carnosic acid did not display direct antibacterial activity, the combination of carnosic acid and meropenem still showed bactericidal activity after the loss of bactericidal effect of meropenem. The experimental results showed that carnosic acid can enhance the antibacterial activity of meropenem against Escherichia coli ZC-YN3. To explore the inhibitory mechanism of carnosic acid against NDM-1, we performed the molecular dynamics simulation and binding energy calculation for the NDM-1-CA complex system. Notably, the 3D structure of the complex obtained from molecular modeling indicates that the binding region of carnosic acid with NDM-1 was not situated in the active region of protein. Due to binding to the allosteric pocket of carnosic acid, the active region conformation of NDM-1 was observed to have been altered. The distance from the active center of the NDM-1-CA complex was larger than that of the free protein, leading to loss of activity. Then, the mutation experiments showed that carnosic acid had lower inhibitory activity against mutated protein than wild-type proteins. Fluorescence experiments verified the results reported above. Thus, our data indicate that carnosic acid is a potential NDM-1 inhibitor and is a promising drug for the treatment of NDM-1 producing pathogens.
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