Phosphonic Acid-Boronic Acid Anhydrides Demonstrate Class A–D β-Lactamase Inhibition

The escalating threat of antibiotic resistance, driven largely by the spread of β-lactamase enzymes, necessitates innovative therapeutic strategies. This work investigates the potential of a novel class of boronic acid-phosphonic acid anhydrides as β-lactamase inhibitors, as well as their oxidative stability and diol-binding ability. Evaluation of two lead compounds, 6 and 12, demonstrated potent inhibition of multiple classes of β-lactamases. Compound 12 was found to be particularly effective, potently inhibiting a broad panel of β-lactamases, including KPC-2 and GC-1, with sustained activity at low micromolar concentrations. These results establish the boronic acid-phosphonic acid anhydride scaffold as a promising and versatile platform for the development of new β-lactamase inhibitors. This discovery provides a valuable foundation for future efforts to combat antibiotic-resistant bacterial infections through rational drug design.