靶向NDM-1锌离子或氨基酸残基的分子集设计合成及其逆转超级细菌耐药性研究

新德里金属-β-内酰胺酶（NDM-1）催生超级细菌，它几乎能水解所有的β-内酰胺类抗生素。因NDM-1亚种多样且活性囊腔宽泛表浅不利于配体结合，目前临床尚无药物使用。因此，研发高效低毒的NDM-1抑制剂逆转超级细菌耐药性成为抗菌感染的研究重点。本项目基于前期研究发现的安全高效的NDM-1抑制剂包括Ebs类似物、生物电子等排体Ebsulfur衍生物、吡咯烷类衍生物以及AMA衍生物，结合NDM-1与hAMP的共晶结构信息，利用虚拟分子对接，创新设计靶向NDM-1锌离子或重要氨基酸残基的分子集，并评价其是否为安全高效的NDM-1抑制剂，是否能够体外、体内逆转NDM-1高表达大肠杆菌Tg1对MEM的耐药性。本项目将确证小分子与NDM-1之间的物理化学作用，明确小分子的NDM-1酶活性调控机制，为NDM-1抑制剂的设计提供理论支持，为开发临床用NDM-1抑制剂，恢复经典抗生素杀菌活性奠定物质基础。

New Delhi metal-β-lactamase (NDM-1) promotes the growth of superbugs, which can hydrolyze almost all β-lactam antibiotics. Due to the diverse subspecies of NDM-1 and the wide and superficial active sites hard to ligand binding, so there is currently no drugs in clinic. Therefore, the development of highly effective and low-toxic NDM-1 inhibitors to reverse the resistance of superbugs has become the focus of research on antibacterial infections. Based on the strcutures of well-known NDM-1 inhibitors including Ebs analogs, Ebsulfur derivatives, pyrrolidine derivatives and AMA analogues, combined with the crystal structure information of NDM-1 and hAMP, using virtual Molecular docking, well-designed molecular set targeting NDM-1 zinc ions or important amino acid residues will be synthesized and evaluated whether they are safe and efficient NDM-1 inhibitors, and whether it can reverse the resistance of MEM by NDM-1 positive E. coli Tg1 in vitro and in vivo. This project is carried out to confirm the physical and chemical effects between small molecules and NDM-1 protein, to clarify the regulation mechanism of small molecule on NDM-1 enzyme and to provide theoretical support for the design of NDM-1 inhibitors. This project can lay the material foundation for the development of NDM-1 inhibitors in clinic use to restore the bactericidal activity of classic antibiotics.