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革兰氏阴性菌的耐药问题日益严峻,已经引起了公众的广泛关注.产新德里金属β-内酰胺酶(NDM-1)的“超级细菌”对几乎所有的β-内酰胺类抗生素耐药.然而临床现有的β-内酰胺酶抑制剂对NDM-1等金属β-内酰胺酶无效,因此,临床上迫切需要有效NDM-1抑制剂.在这项研究中,优化了NDM-1抑制剂的高通量筛选模型.应用该模型筛选NDM-1抑制剂,并从不同来源的化合物样品中筛选得到一种NDM-1的抑制剂IMB-XH1.研究发现IMB-XH1与β-内酰胺类抗生素联合使用可以提高表达NDM-1的大肠埃希菌E.coli BL21 (DE3)(pET-30a(+)-NDM-1)对β-内酰胺类抗生素的敏感性.酶促动力学研究表明IMB-XH1是NDM-1的非竞争性抑制剂.IMB-XH1还具有对其他金属β-内酰胺酶的抑制活性,如IMP-4,ImiS和L1.IMB-XH1作为一种新型的NDM-1抑制剂,值得进一步对其活性评价和作用机制进行深入研究.“,”The problem of drug resistance of Gram-negative bacteria has become increasingly serious and has aroused widespread public concern.The “super bacteria” producing New Delhi metallo-beta-lactamase (NDM-1) are resistant to almost all β-1actam antibiotics.However,clinically existing β-1actamase inhibitors are ineffective against metallo-β-1actamases (MBLs) including NDM-1.Therefore,effective NDM-1 inhibitors are urgently needed.In this study,a high-throughput screening model for NDM-1 inhibitors was optimized and used to screen NDM-1 inhibitors.As a result,IMB-XH1 was screened out as a novel NDM-1 inhibitor from 52 100 compounds of different sources.The combined use of IMB-XH1 can increase the sensitivity of E.coli BL21(DE3) (pET-30a(+)-NDM-1) to β-1actam antibiotics.Enzymatic kinetic studies indicate that IMB-XH1 is a non-competitive inhibitor of NDM-1 and also has inhibitory activity against other MBLs such as IMP-4,ImiS and L1.As a novel NDM-1 inhibitor,its activity and mechanism of action need to be further explored.