Conjugation with Acridines Turns Nuclear Localization Sequence into Highly Active Antimicrobial Peptide

作     者：Wei Zhang Xiaoli Yang Jingjing Song Xin Zheng Jianbo Chen Panpan Ma Bangzhi Zhang Rui Wang 

作者机构：Key Laboratory of Preclinical Study for New Drugs of Gansu Province School of Basic Medical Sciences Lanzhou University Institute of Biochemistry and Molecular Biology School of Life Sciences Lanzhou University 

出 版 物：《Engineering》 (工程（英文）)

年 卷 期：2015年第1卷第4期

页      面：500-505页

核心收录：

学科分类：0710[理学-生物学] 0810[工学-信息与通信工程] 071010[理学-生物化学与分子生物学] 0830[工学-环境科学与工程（可授工学、理学、农学学位）] 0808[工学-电气工程] 07[理学] 0817[工学-化学工程与技术] 0807[工学-动力工程及工程热物理] 071007[理学-遗传学] 0805[工学-材料科学与工程（可授工学、理学学位）] 0703[理学-化学] 0812[工学-计算机科学与技术（可授工学、理学学位）] 

基　　金：the grants from the National Natural Science Foundation of China (81402776 and 81202400) the Key National S&T Progra m "Major New Drug Development" of the Ministry of Science and Technology of China (2012ZX09504001-003) the Fundamental Research Funds for the Central Universities (lzujbky-2014-142 and lzujbky-2015-169) the Specialized Research Fund for the Doctoral Program of Higher Education of China (20130211130005) China Postdoctoral Science Foundation (2013T60896) 

主　　题：核定位序列 抗菌肽 吖啶 高活性 DNA结合 细菌耐药性 共轭 NLS 

摘      要：The emergence of multidrug-resistant bacteria creates an urgent need for alternative antibiotics with new mechanisms of action. In this study, we synthesized a novel type of antimicrobial agent, Ac r_3-NLS, by conjugating hydrophobic acridines to the N-terminus of a nuclear localization sequence(NLS), a short cationic peptide. To further improve the antimicrobial activity of our agent, dimeric(Acr_3-NLS)_2 was simultaneously synthesized by joining two monomeric Acr_3-NLS together via a disulfide linker. Our results show that Acr_3-NLS and especially(Acr_3-NLS)_2 display signifi cant antimicrobial activity against gramnegative and gram-positive bacteria compared to that of the NLS. Subsequently, the results derived from the study on the mechanism of action demonstrate that Acr_3-NLS and(Acr_3-NLS)_2 can kill bacteria by membrane disruption and DNA binding. The double targets—cell membrane and intracellular DNA—will reduce the risk of bacteria developing resistance to Acr_3-NLS and(Acr_3-NLS)_2. Overall, this study provides a novel strategy to design highly eff ective antimicrobial agents with a dual mode of action for infection treatment.