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However, the rise of vancomycin\u2010resistant strains significantly compromises its therapeutic efficacy. To overcome this challenge, recent research has focused on structural modifications of vancomycin using diverse strategies. Herein, the potential of a modification strategy by coupling vancomycin with antimicrobial peptides (AMPs) that have different mechanisms of action is explored. Among the acquired conjugates, Vm\u2010MSI showed a 20.18 fold improvement in antimicrobial activity over vancomycin and a 1.95 fold increase compared to the parent peptide MSI\u201078. Vm\u2010MSI not only delays the development of resistance in vancomycin\u2010resistant\n                    <jats:italic>S. aureus<\/jats:italic>\n                    (VRSA) but also exhibits potent activity against a wide range of Gram\u2010negative bacteria. Additionally, Vm\u2010MSI demonstrated strong synergy with several conventional antibiotics of distinct mechanisms and displayed potent activities in eradicating biofilms and persisters. Mechanistic studies revealed the complex antibacterial mechanisms of Vm\u2010MSI, which hinder the development of bacterial resistance. In vivo, Vm\u2010MSI displayed remarkable therapeutic efficacy in mouse models of VRSA\u2010induced skin infection and multidrug\u2010resistant\n                    <jats:italic>A. baumannii<\/jats:italic>\n                    \u2010induced lung infection. These findings underscore the great potential of Vm\u2010MSI as an effective treatment for infections caused by vancomycin\u2010resistant and Gram\u2010negative bacteria.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503023","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T04:01:38Z","timestamp":1765252898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Vm\u2013MSI: a Vancomycin\u2013Antimicrobial Peptide Conjugate Combating Resistant Bacteria and Broadening the Antimicrobial Spectrum"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuangyu","family":"Li","sequence":"first","affiliation":[{"name":"Yantai Institute of Coastal Zone Research Chinese Academy of Sciences  Yantai Shandong 264003 China"},{"name":"Department of Biopharmaceutical Sciences College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Wang","sequence":"additional","affiliation":[{"name":"Yantai Institute of Coastal Zone Research Chinese Academy of Sciences  Yantai Shandong 264003 China"},{"name":"Department of Biopharmaceutical Sciences College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhuang","family":"Shi","sequence":"additional","affiliation":[{"name":"Yantai Institute of Coastal Zone Research Chinese Academy of Sciences  Yantai Shandong 264003 China"},{"name":"Department of Biopharmaceutical Sciences College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[{"name":"Yantai Institute of Coastal Zone Research Chinese Academy of Sciences  Yantai Shandong 264003 China"},{"name":"Department of Biopharmaceutical Sciences College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duxin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutical Sciences College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutical Sciences College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu 215004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1385-4470","authenticated-orcid":false,"given":"Yipeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Yantai Institute of Coastal Zone Research Chinese Academy of Sciences  Yantai Shandong 264003 China"},{"name":"Department of Biopharmaceutical Sciences College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2022.114378"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2677"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200903924"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.2.375-381.2001"},{"key":"e_1_2_9_6_1","volume":"12","author":"Sujatha S.","year":"2012","journal-title":"Interdiscip. 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