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 1 e 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 haemolysis and antibacterial activity. However, 1 e potentiated the efficacy of β-lactam antibiotics (e. g., meropenem and ceftazidime) against KPC-2-expressing resistant Klebsiella pneumonia by up to 256-fold.