一种新型KPC-2抑制剂: PHT427

doi:10.5246/jcps.2023.12.079

中国药学(英文版) ›› 2023, Vol. 32 ›› Issue (12): 989-997.DOI: 10.5246/jcps.2023.12.079

一种新型KPC-2抑制剂: PHT427

李晓辉¹, 王倩², 刘琛楠³, 韩江雪¹, 刘思含¹, 刘天俊¹, 王倩¹, 关艳¹, 肖春玲¹, 王潇¹^,^*(), 刘忆霜¹^,^*()

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

收稿日期:2023-07-24 修回日期:2023-08-16 接受日期:2023-09-21 出版日期:2024-01-04 发布日期:2023-12-31
通讯作者: 王潇, 刘忆霜
作者简介:
+ Tel.: +86-10-63020226, E-mail: wangxiao_1107@163.com
+ E-mail: liuys@imb.pumc.edu.cn
基金资助:
CAMS Innovation Fund for Medical Sciences (Grant No. 2021-I2M-1-028), and the National Natural Science Foundation of China (Grant No. 32141003, 81872913 and 81903678).

PHT427 functions as a novel inhibitor of KPC-2

Xiaohui Li¹, Qian Wang², Chennan Liu³, Jiangxue Han¹, Sihan Liu¹, Tianjun Liu¹, Qian Wang¹, Yan Guan¹, Chunling Xiao¹, Xiao Wang¹^,^*(), Yishuang Liu¹^,^*()

1 National Key Laboratory for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
2 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, Shandong, China
3 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing 101149, China

Received:2023-07-24 Revised:2023-08-16 Accepted:2023-09-21 Online:2024-01-04 Published:2023-12-31
Contact: Xiao Wang, Yishuang Liu

摘要/Abstract

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2.04 μM, 并且与美罗培南联用对大肠杆菌BL21(DE3)/pET28a(+)-blaKPC-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。

关键词: KPC-2, PHT427, 抗生素耐药, 抑制剂

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:

李晓辉, 王倩, 刘琛楠, 韩江雪, 刘思含, 刘天俊, 王倩, 关艳, 肖春玲, 王潇, 刘忆霜. 一种新型KPC-2抑制剂: PHT427[J]. 中国药学(英文版), 2023, 32(12): 989-997.

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.

图/表 6

参考文献 23

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一种新型KPC-2抑制剂: PHT427

PHT427 functions as a novel inhibitor of KPC-2

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