Structure-based approach for identification of novel phenylboronic acids as serine-beta-lactamase inhibitors

beta-Lactamases are bacterial enzymes conferring resistance to beta-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of similar to 1400 boronic acids as potential AmpC beta-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant beta-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K (i) value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase.