文献类型：期刊文献

英文题名：Postmodification of Daptomycin at Tryptophan Enables the Discovery of Aryl-Daptomycin Antibiofilm Activity against MRSA

作者：Yan, Tiantian[1,2];Li, Jingyue[1,2];Li, Yiping[1,2];Ma, Bingzi[1,2];Jiao, Ruoyan[1,2];Cai, Xinyu[1,2];Liu, Xiaoyu[3];Yang, Weili[1,2];Dai, Wei[1,2];Bai, Haiya[1,2,4];Yang, Wenle[1,2];Miao, Xiaokang[1,2];Ran, Junpeng[1,2];Bao, Guangjun[1,2];Xie, Junqiu[1,2];Sun, Wangsheng[1,2];Wang, Rui[1,2,5]

第一作者：Yan, Tiantian

通信作者：Bao, GJ[1];Xie, JQ[1];Sun, WS[1];Bao, GJ[2];Xie, JQ[2];Sun, WS[2]

机构：[1]Lanzhou Univ, Chinese Acad Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Sch Basic Med Sci,2019RU066, Lanzhou 730000, Gansu, Peoples R China;[2]Lanzhou Univ, Chinese Acad Med Sci, Res Unit Peptide Sci, 2019RU066, Lanzhou 730000, Gansu, Peoples R China;[3]Gansu Univ Chinese Med, Clin Med Coll 1, Lanzhou 730000, Peoples R China;[4]Gansu Prov Matern & Child Care Hosp, Gansu Prov Cent Hosp, Lanzhou 730000, Peoples R China;[5]Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

第一机构：Lanzhou Univ, Chinese Acad Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Sch Basic Med Sci,2019RU066, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Chinese Acad Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Sch Basic Med Sci,2019RU066, Lanzhou 730000, Gansu, Peoples R China;[2]corresponding author), Lanzhou Univ, Chinese Acad Med Sci, Res Unit Peptide Sci, 2019RU066, Lanzhou 730000, Gansu, Peoples R China.

年份：2026

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;Scopus(收录号：2-s2.0-105041513363);WOS:【SCI-EXPANDED(收录号:WOS:001776237500001)】；

基金：This study was supported by the National Natural Science Foundation of China (Nos. 82574377, 22577046, 22307052, China), the Shenzhen Medical Research Fund (No. D2503007, China), the Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (JYB2025XDXM609), the Fundamental Research Funds for the Central Universities (No. lzujbky-2024-it24, lzujbky-2025-ou14, China), and the Gansu Science and Technology Program (25JRRA665, 26JRRA172, China).

语种：英文

摘要：Biofilm-related infections pose a growing global health threat and demand novel therapeutic agents. Although Daptomycin is effective against Gram-positive bacteria and biofilms, the emergence of resistant strains necessitates next-generation derivatives. Herein, a library of aryl-Daptomycin was successfully constructed by postmodification of Daptomycin at the tryptophan residue. The lead compound 1i exhibited improved antibacterial activity, antibiofilm efficacy, and stability compared with Daptomycin, and also showed rapid killing of both planktonic and persister cells. In vivo studies, 1i significantly reduced drug-resistant bacterial counts and biofilm burdens in mouse models of skin wound infection and catheter-related biofilm infection. Mechanistic studies revealed that it exerts antibacterial activity by inducing membrane depolarization and disruption, while it inhibits biofilm formation by downregulating the ica gene and blocking the agr system. Moreover, molecular dynamics simulations confirmed the higher tetrameric stability of 1i compared with Daptomycin. Collectively, 1i represents a promising candidate for clinical treatment of bacterial infections.