具有胞内累积性的MBL/SBL双重抑制剂的设计、优化及抗碳青霉烯耐药菌活性研究

The carbapenem-resistant bacteria with co-expression of metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) have posed a serious threat to public health, development of dual inhibitors of MBL and SBL has potential to overcome drug resistance to this kind of superbugs. However, due to the structural and mechanistic differences between MBL and SBL, and the emergence and spread of MBL/SBL co-expressed carbapenem-resistant bacteria within the last couple of years, there have been very few reports of MBL/SBL dual inhibitors to date. In previous work, we identified a number of new MBL inhibitors and obtained their complex crystal structures, on basis of which we designed and discovered four new types of MBL/SBL dual inhibitors using our previously developed methods and pharmacophore models. Next, we will carry out structural optimization on these four types of compounds through compound accumulation rules, crystallographic analysis, drug design, chemical synthesis, biological activity testing, and off-target research to systematically study their structure-dual inhibition activity relationship and structure-intracellular accumulation relationship, with aim to obtain the dual inhibitors with high potency and high intracellular accumulation. Then, we will assess the antibacterial activity and restoration of carbapenem activity of the selected dual inhibitors against the MBL/SBL co-expressed carbapenem-resistant bacteria in vitro and in vivo, and we will further assess their druggability. The smooth implementation of this project is expected to lay the foundation for the innovative drug discovery & development combating MBL/SBL co-expressed carbapenem-resistant bacteria.

金属β-内酰胺酶（MBL）和丝氨酸β-内酰胺酶（SBL）共表达碳青霉烯耐药菌已威胁到人类生命健康，研发MBL/SBL双重抑制剂有望克服此类超级细菌耐药。然而，因MBL和SBL结构与催化机制不同且共表达碳青霉烯耐药菌近几年才不断出现和蔓延，迄今鲜有双重抑制剂报道。前期，在获得新型MBL抑制剂及复合物晶体结构后，申请人采用自主发展的药物设计方法、药效团模型等，设计并发现了四类骨架新颖的MBL/SBL双重抑制先导化合物。接下来，本项目将根据胞内累积规则，通过晶体结构测定、药物设计、化学合成、活性测试和脱靶作用评价等对四类骨架进行结构优化，从而系统揭示其结构-双重抑制活性和结构-胞内累积性关系，以期获得高活性、高胞内累积性的双重抑制剂；再评价优选化合物体内外逆转MBL/SBL共表达耐药菌对碳青霉烯耐药的活性及成药性。本项目的顺利实施有望为抗MBL/SBL共表达碳青霉烯耐药菌的创新药物研究奠定基础。

金属β-内酰胺酶（MBL）和丝氨酸β-内酰胺酶（SBL）共表达碳青霉烯耐药菌已威胁到人类生命健康，研发MBL/SBL双重抑制剂有望克服此类超级细菌耐药。然而，因MBL和SBL结构与催化机制不同且共表达碳青霉烯耐药菌近几年才不断出现和蔓延，迄今尚无MBL/SBL双重抑制剂批准上市。本项目发展了锚定药效团AncPhore程序、药效团融合策略、点击衍生策略等，针对临床重要的MBL/SBL亚型，综合利用这些方法和策略开展了创新先导发现与药物设计，发现了巯基酰胺硼酸类、苯并五元环硼酸酯类、噻唑胺-二氮杂双环辛酮等多种不同骨架的MBL/SBL双重抑制剂，并深入开展了结构优化、活性测试、复合物晶体结构研究、药效学和药代动力学研究等，获得了具有潜在成药性的MBL/SBL双重抑制剂，为靶向MBL/SBL克服β内酰胺抗生素耐药的创新药物研发提供了创新先导和研究基础。以通讯作者在J Med Chem等杂志发表基金标注SCI论文15篇，其中影响因子大于10论文3篇；受邀在Trends Microb和Med Res Rev期刊撰写相关综述论文。以第一发明人申请相关中国发明专利7项，其中2项已授权。