A Review on the Structural Evolution and Clinical Evidence of Boronic Acid β-Lactamase Inhibitors

The spread of carbapenem-resistant Gram-negative bacilli has made β-lactam/β-lactamase inhibitor (BLI) combinations central to therapy. Boronic acids are the only BLI class whose chemistry can in principle reach all four Ambler classes, boron forms a tetrahedral adduct with the catalytic serine and can also coordinate the zinc ions of metallo-β-lactamases. PubMed/MEDLINE and Web of Science were searched to 30 September 2026, together with ClinicalTrials.gov and the Protein Data Bank, for structural, biochemical, surveillance, and clinical data on vaborbactam, taniborbactam, and xeruborbactam. The three generations are compared across enzyme classes, the diazabicyclooctane durlobactam is used as a mechanistic comparator, and the pivotal phase 3 trials are appraised against the requirements of enzyme-guided therapy. The scaffold has advanced from KPC-selective monocyclic to bicyclic compounds that inhibit serine and subclass B1 metallo-β-lactamases in vitro at nanomolar concentrations, but this breadth remains largely unrealized clinically. Reported potencies differ by one to two orders of magnitude between laboratories, coverage of IMP, SPM, and subclass B3 enzymes is incomplete, and no registrational trial has been designed around carbapenemase genotype. Partner β-lactam selection and trial design now constrain the field more than target engagement does.