2. Academic Validation
  3. 2-Carboxyquinoline Boronic Acids as Highly Potent KPC Inhibitors

2-Carboxyquinoline Boronic Acids as Highly Potent KPC Inhibitors

  • ChemMedChem. 2024 Dec 27:e202400901. doi: 10.1002/cmdc.202400901.
Zheng Ma 1,  Ge Cui 1,  Lijie Dou 1,  Fangfang Chen 1,  Hexin Xie 1
Affiliations

Affiliation

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China.
PMID: 39727024 DOI: 10.1002/cmdc.202400901
Abstract

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.

Keywords

antibiotic resistance; carbapenemase; inhibitor; β-lactamase.

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