Tricyclic boronic acids as broad-spectrum serine and metallo-β-lactamase inhibitors with in vitro activity against acinetobacter baumannii

Introduction With β-lactams remaining the most widely prescribed antibacterials worldwide, their continuing clinical efficacy remains an important therapeutic goal. Rapid spread of serine and metallo-ß-lactamases (SBLs and MBLs, respectively), which can inactivate β-lactams, is increasingly threatening this objective. Finding clinically useful inhibitors of MBLs, for which no FDA approved treatment currently exists, is of interest. Areas covered This article concisely reviews structurally novel xeruborbactam-inspired tricyclic boronates (reported in US 2025/0223303) with promising inhibitory activities in vitro. The literature search was conducted using SciFinder and Patentscope. By introducing novel thioether-based C5 sidechains onto the previously optimized bicyclic boronate core, the inventors explored novel chemical space yielding SBL/MBL inhibitors with seemingly improved activities against carbapenem-resistant (CR) Escherichia coli, Klebsiella pneumoniae, and, importantly, Acinetobacter baumannii, when used in combination with meropenem and/or biapenem (at least with respect to taniborbactam, i.e. boronate inhibitor in late-stage clinical development). Expert opinion Due to the major societal importance of β-lactams for modern medicine, and the clearly demonstrated clinical potential of functionalized cyclic boronates as potent dual-acting SBL/MBL inhibitors when used in combination therapies, there is ample opportunity and scope for continued investigation of this pharmacophore, particularly in the context of discovering new therapeutic options for CR infections.