2‐Carboxyquinoline Boronic Acids as Highly Potent KPC Inhibitors

The expression of Klebsiella pneumoniae carbapenemase (KPC), a type of carbapenem‐hydrolyzing β‐lactamase, in Gram‐negative bacteria has caused significant bacterial resistance to carbapenems, the antibiotic of last resort. Herein, we describe the discovery of 2‐carboxyquinoline boronic acids as inhibitor of KPC. We have identified fluoro‐substituted carboxyquinoline boronic acids 1e as the most potent inhibitor, with an IC50 of 8.3 nM for KPC‐2, while this compound is significantly less efficient at reducing the activity of other β‐lactamases. This compound proved to have low cytotoxicity towards mammalian cells, as well as low hemolysis and antibacterial activity. However, 1e potentiated the efficacy of β‐lactam antibiotics (e.g., meropenem and ceftazidime) against KPC‐2‐expressing resistant Klebsiella pneumonia by up to 256‐fold.