Bicyclic beta-Lactam Antibiotics as Poor Substrates for Metallo-beta-lactamases

描述（由申请方提供）：β-内酰胺酶介导的细菌耐药性继续向更广泛的底物谱发展，包括最有效的β-内酰胺抗生素碳青霉烯类。新的碳青霉烯酶包括丝氨酸水解酶，如A类KPC β-内酰胺酶，以及B类金属β-内酰胺酶（MBL），如NDM-1，其自五年前出现以来已在全球传播.该项目将制备和评价手性取代的双环β-内酰胺，包括碳青霉烯类和青霉烯类，以评估进一步开发这些β-内酰胺支架作为MBL的不良底物和/或抑制剂的潜力。该项目由关键青霉素结合蛋白（PBP）的酰基酶的最新结构数据指导，特别是包括来自铜绿假单胞菌和鲍曼不动杆菌的PBP 3，以及水解抗生素与MBL的复合物，特别是包括NDM-1的复合物。待修饰的位置代表由于合成困难而未被广泛研究的位置。包括Peter Oeschlaeger，Robert Bonomo，German Bou和Natalie Strynadka在内的几位合作者将分别提供有关新合成抗生素和MBL相互作用的动力学，微生物学和结构信息。

DESCRIPTION (provided by applicant): ß-Lactamase-mediated bacterial resistance continues to evolve toward a broader substrate spectrum, including the most potent ß-lactam antibiotics, the carbapenems. New carbapenemases include both serine hydrolases, such as the class A KPC ß-lactamases, as well as the class B metallo-ß-lactamases (MBLs), such as NDM-1, which has spread globally since its appearance just five years ago. This project will prepare and evaluate atypically substituted bicyclic ß-lactams, including both carbapenems and penams, to assess the potential to further develop these ß-lactam scaffolds as poor substrates and/or inhibitors of the MBLs. The project is guided by recent structural data on acyl-enzymes of key penicillin-binding proteins (PBPs), particularly including PBP3 from Pseudomonas aeruginosa and Acinetobacter baumannii, as well as complexes of hydrolyzed antibiotics with the MBLs, particularly including complexes of NDM-1. The positions to be modified represent positions that have not been extensively examined, due to synthetic difficulty. Several collaborators including, Peter Oeschlaeger, Robert Bonomo, German Bou, and Natalie Strynadka will provide kinetic, microbiological, and structural information, respectively, on the interactions of the newly synthesized antibiotics and the MBLs.