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 

机构地区：[1]Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University [2]Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University

出　　处：《Engineering》2015年第4期500-505,共6页工程（英文）

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)

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.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, Acr3-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 （Acr3-NLS）2 was simultaneously synthesized by joining two monomeric Acr3-NLS together via a disulfide linker. Our results show that Acr3-NLS and especially （Acr3- NLS）2 display significant antimicrobial activity against gram- negative and gram-positive bacteria compared to that of the NLS. Subsequently, the results derived from the study on the mechanism of action demonstrate that Acr3-NLS and （Acr3- 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 Acr3-NLS and （Acr3-NLS）2. Overall, this study provides a novel strategy to design highly effective antimicrobial agents with a dual mode of action for infection treatment.

关 键 词：ACRIDINE nuclear localization sequence CONJUGATE antimicrobial activity mechanism of action 

分 类 号：Q756[生物学—分子生物学] Q516