Conjugation with Acridines Turns Nuclear Localization Sequence into Highly Active Antimicrobial Peptide
Conjugation with Acridines Turns Nuclear Localization Sequence into Highly Active Antimicrobial Peptide
复制标题
与吖啶缀合将核定位序列转化为高活性抗菌肽
DOI：
10.15302/j-eng-2015106
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发表时间：
2015-12
期刊：
影响因子：
12.8
通讯作者：
Rui Wang
中科院分区：
文献类型：
--
作者：
Wei Zhang;Xiaoli Yang;Jingjing Song;Xin Zheng;Jianbo Chen;Panpan Ma;Bangzhi Zhang;Rui Wang
耐多药细菌的出现迫切需要具有新的作用机制的替代抗生素。在这项研究中，我们通过将疏水吖啶化合物偶联到一个短阳离子肽的核定位序列（NLS）的n端，合成了一种新型抗菌剂Acr3-NLS。为了进一步提高该药剂的抗菌活性，我们将两个单体Acr3-NLS通过二硫化物连接在一起，同时合成了二聚体（Acr3-NLS）2。结果表明，与NLS相比，Acr3-NLS，特别是（Acr3-NLS）2对革兰氏阴性菌和革兰氏阳性菌具有显著的抑菌活性。随后，对作用机制的研究结果表明，Acr3-NLS和（Acr3-NLS）2可以通过破坏膜和结合DNA杀死细菌。细胞膜和细胞内dna的双重靶标将降低细菌对Acr3-NLS和（Acr3-NLS）2产生耐药性的风险。总的来说，这项研究提供了一种新的策略来设计具有双重作用模式的高效抗菌药物用于感染治疗。
ABSTRACT 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.
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影响因子：
4.8
作者：
Kondejewski, LH;Jelokhani-Niaraki, M;Hodges, RS
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
Song, Jingjing;Zhang, Yun;Wang, Rui
通讯作者：
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影响因子：
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作者：
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通讯作者：
Avison, MB