靶向毒素蛋白HipA的抑制剂能够减轻细菌的多药耐药性
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- 英文论文题名：Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters
- 论文作者：裴剑锋 ; 李佟清 ; 来鲁华
- 英文论文作者：JianfengPei ; Tongqing Li ; Luhua Lai ; Center for Quantitative Biology ; Academy for Advanced Interdisciplinary Studies ; Peking University ; BNLMS ; State Key Laboratory for Structural Chemistry of Unstable and Stable Species ; College of Chemistry and Molecular Engineering ; Peking University
- 年：2016
- 作者机构：北京大学前沿交叉学科研究院定量生物学中心;北京大学化学与分子工程学院;
- 论文关键词：持留菌 ; 毒素-抗毒素模块 ; HipA
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十五分会：化学信息学与化学计量学
- 语种：中文
- 分类号：TQ460.1
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十五分会 ; 化学信息学与化学计量学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：206k
- 原文格式：D
- 会议级别：全国
摘要
持留菌是细菌群体中一小部分没有发生基因突变,但是对多种抗生素耐药的群体,是导致抗菌治疗失败和细菌多药耐药性产生的主要原因之一。持留菌的产生与毒素-抗毒素系统具有较强的关联性。本研究中我们针对毒素蛋白HipA进行了基于结构的药物设计,用虚拟筛选方法首次发现了4个HipA的小分子抑制剂。其中活性最高的化合物与HipA的结合KD为270±90nM。在对大肠杆菌作用的测试中,这个小分子对于青霉素筛选的EC_(50)为46±2μM,对于卡拉霉素筛选的EC_(50)为28±1μM。我们的结果表明,设计靶向毒素-抗毒素系统的抑制剂,能够不依赖抗生素类型地减轻细菌的多药耐药性。
Persisters are a small fraction of drug-tolerant bacteria without any genotype variations.Their existence in many life-threatening infectious diseases presents a major challenge to antibiotic therapy.Persistence is highly related to toxin-antitoxin modules.HipA(high persistence A) was the first toxin found to contribute to Escherichia coli persistence.In this study,we used structure-based virtual screening for HipA inhibitors discovery and identified several novel inhibitors of HipA that remarkably reduced E.coli persistence.The most potent one decreased the persister fraction by more than five-fold with an in vitro KD of 270 ± 90 nM and an ex vivo EC50 of46 ± 2 and 28 ± 1 μM for ampicillin and kanamycin screening,respectively.These findings demonstrated that inhibition of toxin can reduce bacterial persistence independent of the antibiotics used and provided a framework for persistence treatment by interfering with the toxin-antitoxin modules.
Persisters are a small fraction of drug-tolerant bacteria without any genotype variations.Their existence in many life-threatening infectious diseases presents a major challenge to antibiotic therapy.Persistence is highly related to toxin-antitoxin modules.HipA(high persistence A) was the first toxin found to contribute to Escherichia coli persistence.In this study,we used structure-based virtual screening for HipA inhibitors discovery and identified several novel inhibitors of HipA that remarkably reduced E.coli persistence.The most potent one decreased the persister fraction by more than five-fold with an in vitro KD of 270 ± 90 nM and an ex vivo EC50 of46 ± 2 and 28 ± 1 μM for ampicillin and kanamycin screening,respectively.These findings demonstrated that inhibition of toxin can reduce bacterial persistence independent of the antibiotics used and provided a framework for persistence treatment by interfering with the toxin-antitoxin modules.
引文
[1]Li,T.;Yin,N.;Liu,H.;Pei,J;Lai,L.ACS Med.Chem.Lett.2016,DOI:10.1021/acsmedchemlett.5b00420