一种新型KPC-2抑制剂:PHT427  

PHT427 functions as a novel inhibitor of KPC-2

作　　者：李晓辉 王倩[2] 刘琛楠 韩江雪[1] 刘思含 刘天俊 王倩 关艳[1] 肖春玲[1] 王潇[1] 刘忆霜[1] Xiaohui Li;Qian Wang;Chennan Liu;Jiangxue Han;Sihan Liu;Tianjun Liu;Qian Wang;Yan Guan;Chunling Xiao;Xiao Wang;Yishuang Liu(National Key Laboratory for Screening New Microbial Drugs,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;Key Laboratory of Marine Drugs,Ministry of Education,School of Medicine and Pharmacy,Ocean University of China,Qingdao 266003,Shandong,China;Beijing Key Laboratory of Drug Resistance Tuberculosis Research,Beijing Chest Hospital,Beijing Tuberculosis and Thoracic Tumor Research Institute,Capital Medical University,Beijing 101149,China)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所,国家新药(微生物)筛选实验室,北京100050 [2]中国海洋大学药学院海洋药物教育部重点实验室,山东青岛266003 [3]首都医科大学附属北京胸科医院,结核病胸部肿瘤研究所,药物学研究室,北京101149

出　　处：《Journal of Chinese Pharmaceutical Sciences》2023年第12期989-997,共9页中国药学（英文版）

基　　金：CAMS Innovation Fund for Medical Sciences (Grant No. 2021-I2M-1-028);the National Natural Science Foundation of China (Grant No. 32141003, 81872913 and 81903678)。

摘　　要：KPC-2型β-内酰胺酶对超广谱头孢菌素和碳青霉烯类抗生素具有耐药性,并已成为治疗革兰氏阴性菌感染的全球重大威胁,因此寻找新型抗菌剂和新的抗感染策略非常重要。我们前期经筛选发现PHT427是一种有效的NDM-1抑制剂,进一步研究发现其对KPC-2也有明显的抑制活性。结果显示PHT427能够显著抑制KPC-2,IC50值为2.04μM,并且与美罗培南联用对大肠杆菌BL21(DE3)/p ET28a(+)-bla KPC-2具有明显的协同作用。荧光淬灭和SPR结果表明PHT427能够与KPC-2发生相互作用。分子对接与定点突变的结果进一步表明Arg220、Thr235和Thr237是促进这种相互作用的关键氨基酸残基。研究表明PHT427是一种具有潜力的KPC-2抑制剂并且能够协助碳青霉烯类抗生素抑制KPC-2产生菌。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)/p ET28a(+)-bla KPC-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.

关 键 词：KPC-2 PHT427 抗生素耐药 抑制剂 

分 类 号：R965[医药卫生—药理学]