文献类型：期刊文献

英文题名：Switching from membrane disrupting to membrane crossing, an effective strategy in designing antibacterial polypeptide

作者：Zhang, Haodong[1];Chen, Qi[2];Xie, Jiayang[2];Cong, Zihao[2];Cao, Chuntao[2];Zhang, Wenjing[2];Zhang, Donghui[1,2];Chen, Sheng[2];Gu, Jiawei[2];Deng, Shuai[2];Qiao, Zhongqian[2];Zhang, Xinyue[2];Li, Maoquan[3];Lu, Ziyi[2];Liu, Runhui[1,2]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Sch Mat Sci & Engn, Key Lab Ultrafine Mat,Minist Educ,Frontiers Sci Ct, Shanghai 200237, Peoples R China;[3]Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Intervent & Vasc Surg, Shanghai 200072, Peoples R China

年份：2023

卷号：9

期号：4

外文期刊名：SCIENCE ADVANCES

收录：;EI(收录号：20230613551658);WOS:【SCI-EXPANDED(收录号:WOS:000934904500001)】；

基金：This research was supported by the National Natural Science Foundation of China for Innovative Research Groups (no. 51621002) , the National Natural Science Foundation of China (nos. 22075078 and 21861162010) , the National Key Research and Development Program of China (2022YFC2303100) , Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission) , Program of Shanghai Academic/Technology Research Leader (20XD1421400) , Research Program of State Key Laboratory of Bioreactor Engineering, and the Fundamental Research Funds for the Central Universities (JKD01211520) .

语种：英文

外文关键词：Amino acids - Antimicrobial agents - Bacteria - Health risks - Membranes - Polypeptides

摘要：Drug-resistant bacterial infections have caused serious threats to human health and call for effective antibacterial agents that have low propensity to induce antimicrobial resistance. Host defense peptide-mimicking peptides are actively explored, among which poly-beta-L-lysine displays potent antibacterial activity but high cytotoxicity due to the helical structure and strong membrane disruption effect. Here, we report an effective strategy to optimize antimicrobial peptides by switching membrane disrupting to membrane penetrating and intracellular targeting by breaking the helical structure using racemic residues. Introducing beta-homo-glycine into poly-beta-lysine effectively reduces the toxicity of resulting poly-beta-peptides and affords the optimal poly-beta peptide, beta Lys50HG50, which shows potent antibacterial activity against clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) and MRSA persister cells, excellent biosafety, no antimicrobial resistance, and strong therapeutic potential in both local and systemic MRSA infections. The optimal poly-beta-peptide demonstrates strong therapeutic potential and implies the success of our approach as a generalizable strategy in designing promising antibacterial polypeptides.