While the cephalosporin class of beta-lactams was the mainstay of treatment in the 1980s, the dissemination of extended-spectrum beta-lactamases (ESBLs) over the past two decades has dramatically weakened the utility of this class and brought about a corresponding reliance on the carbapenems. Although carbapenems are widely recognized as a safe and effective class of antimicrobials, carbapenem-resistant Enterobacteriaceae (CRE) due primarily to the <i>Klebsiella pneumoniae</i> carbapenemase (KPC) now threatens the usefulness of all beta-lactam antibiotics. Recognizing the long history of boronic acids as serine protease inhibitors, we set out to identify a potent inhibitor of the KPC enzyme for use in combination with a carbapenem. Our initial designs based on literature inhibitors were refined by modeling; synthesis and optimization led to RPX7009, now in Phase 3 clinical trials in combination with meropenem. Further efforts to expand the spectrum of beta-lactamase inhibition led to RPX7063, which in addition to the desired broader spectrum (inhibition of Class A and Class C enzymes) exhibits intrinsic oral bioavailability. Most recently, the spectrum of inhibition has been expanded to include metallo beta-lactamases including NDM-1. X-ray crystal structures of these agents bound to serine and metallo beta-lactamases have validated our design hypotheses.

Cyclic boronic acid beta-lactamase inhibitors

251st National Meeting (2016)

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