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 <b>CB1</b> 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 <b>CB1</b>, 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. <b>YL6113</b> 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.