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Antimicrobial peptides (AMPs), with broad\u2010spectrum activity and low propensity for resistance development, show promise as effective antibiotic adjuvants to reverse multidrug\u2010resistance in bacteria. Herein, it is uncovered that a potent and non\u2010toxic AMP termed GN1 substantially resensitizes MRSA to multiple <jats:italic>\u03b2<\/jats:italic>\u2010lactam antibiotics at low concentrations. Mechanistic studies indicate that GN1 functions by suppressing both the production and enzymatic activity of MRSA\u2010associated resistance determinants, including penicillin\u2010binding protein 2a (PBP2a) and <jats:italic>\u03b2<\/jats:italic>\u2010lactamase. Additionally, GN1 exhibits a robust anti\u2010virulence profile by inhibiting MRSA biofilm formation and staphyloxanthin production. Furthermore, GN1 induces bacterial metabolic perturbation, resulting in glutamate accumulation and oxidative damage. Importantly, the combination of GN1 with <jats:italic>\u03b2<\/jats:italic>\u2010lactam antibiotics effectively mitigates MRSA\u2010induced infections in the animal infection models. Collectively, these findings suggest that GN1 represents a potent <jats:italic>\u03b2<\/jats:italic>\u2010lactam adjuvant and anti\u2010virulence agent, offering a safe and versatile solution to combat MRSA infections.<\/jats:p>","DOI":"10.1002\/advs.202416260","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T05:36:07Z","timestamp":1740029767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Non\u2010Membrane Active Peptide Resensitizes MRSA to <i>\u03b2<\/i>\u2010Lactam Antibiotics and Inhibits <i>S. aureus<\/i> Virulence"],"prefix":"10.1002","volume":"12","author":[{"given":"Jingru","family":"Shi","sequence":"first","affiliation":[{"name":"Jiangsu Co\u2010innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou 225009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou 225009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Kong","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou 225009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiyu","family":"Yu","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou 225009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyan","family":"Lv","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou 225009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou 225009 China"},{"name":"Joint International Research Laboratory of Agriculture and Agri\u2010Product Safety the Ministry of Education of China Yangzhou University  Yangzhou 225009 China"},{"name":"Institute of Comparative Medicine Yangzhou University  Yangzhou 225009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9622-6471","authenticated-orcid":false,"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou 225009 China"},{"name":"Joint International Research Laboratory of Agriculture and Agri\u2010Product Safety the Ministry of Education of China Yangzhou University  Yangzhou 225009 China"},{"name":"Institute of Comparative Medicine Yangzhou University  Yangzhou 225009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.44.1.108-118.2006"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00134-14"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.99.2579.452"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.6.1549-1555.2000"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112312"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02723"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.183.22.6525-6531.2001"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30605-4"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8NP00031J"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.56205"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0058-8"},{"key":"e_1_2_9_11_1","first-page":"368","author":"Lazzaro B. 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