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.