PHT427 functions as a novel inhibitor of KPC-2

doi:10.5246/jcps.2023.12.079

Abstract

Abstract:

KPC-2 β-lactamases are a significant global concern as they confer resistance to extended-spectrum cephalosporins and carbapenems, thereby complicating the treatment of Gram-negative bacterial infections. This has underscored the urgent need for novel antimicrobial agents and innovative anti-infective strategies. Our prior research has identified PHT427 as a potent NDM-1 inhibitor. Subsequent investigations revealed its marked inhibitory activity against KPC-2. Specifically, PHT427 inhibited KPC-2 with an IC50 value of 2.04 μM and exhibited a synergistic effect against Escherichia coli BL21(DE3)/pET28a(+)-blaKPC-2 when combined with meropenem. Fluorescence quenching and SPR analyses suggested a direct interaction between PHT427 and KPC-2. Molecular docking and targeted mutagenesis studies further highlighted Arg220, Thr235, and Thr237 as critical residues facilitating this interaction. In summary, our data proposed PHT427 as a promising KPC-2 inhibitor that could potentiate the efficacy of carbapenem antibiotics against KPC-2-producing bacteria.

Key words: KPC-2, PHT427, Antibiotics resistance, Inhibitor

Supporting:

Xiaohui Li, Qian Wang, Chennan Liu, Jiangxue Han, Sihan Liu, Tianjun Liu, Qian Wang, Yan Guan, Chunling Xiao, Xiao Wang, Yishuang Liu. PHT427 functions as a novel inhibitor of KPC-2[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(12): 989-997.

Figures/Tables 6

References 23

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