Structural Optimization of Bicyclic Oxo-Boronates as Dual Metallo- and Serine-β-Lactamase Inhibitors

Gram-negative bacterial resistance to β-lactam antibiotics is a growing clinical problem, largely driven by the production of metallo-β-lactamases (MBLs) and serine-β-lactamases (SBLs). Developing dual inhibitors targeting both MBLs and SBLs has emerged as a focus in the fight against β-lactam resistance. We previously identified the bicyclic oxo-boronate CB1 as a dual MBL/SBL inhibitor through molecular generation based on the binding mode of carbapenem tetrahedral intermediates. Herein, we report the structural optimization of CB1, yielding new bicyclic oxo-boronates with potent dual MBL/SBL inhibition, some of which could potentiate Meropenem efficacy against carbapenem-resistant Gram-negative superbugs. X-ray crystallography revealed a common binding mode of bicyclic oxo-boronates with VIM-2/NDM-1 MBL and OXA-48 SBL, mimicking the binding of carbapenem intermediates. YL6113 exhibited pharmacokinetic characteristics similar to Meropenem and manifested efficacy when combined with Meropenem in a murine sepsis model. This work provides the basis for developing oxo-boronate-based inhibitors targeting MBLs/SBLs and other relevant targets.革兰氏阴性菌对β-内酰胺类抗生素的耐药性已成为日益严峻的临床难题，其主要驱动因素为金属β-内酰胺酶（metallo-β-lactamases, MBLs）与丝氨酸β-内酰胺酶（serine-β-lactamases, SBLs）的产生。靶向MBLs与SBLs的双重抑制剂开发，现已成为对抗β-内酰胺类耐药性的研究焦点。本团队此前基于碳青霉烯类四面体中间体的结合模式，通过分子生成策略鉴定出双环氧硼酸盐CB1作为MBL/SBL双重抑制剂。本文报道了针对CB1的结构优化工作，获得了一系列兼具强效MBL/SBL双重抑制活性的新型双环氧硼酸盐类化合物；其中部分化合物可显著增强美罗培南（Meropenem）对碳青霉烯类耐药革兰氏阴性超级细菌的抗菌功效。X射线晶体学（X-ray crystallography）研究揭示，双环氧硼酸盐类化合物与VIM-2/NDM-1型MBL及OXA-48型SBL存在通用结合模式，其结合方式模拟了碳青霉烯类中间体的结合过程。化合物YL6113展现出与美罗培南相似的药代动力学特性，且在小鼠脓毒症模型中与美罗培南联合给药时，表现出显著的治疗效果。本研究为开发靶向MBLs/SBLs及其他相关靶点的氧硼酸盐类抑制剂提供了重要基础。