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Cationic lipopeptides have attracted much attention due to their strong antimicrobial activity, broad\u2010spectrum and low resistance tendency. Herein, a library of fluoro\u2010lipopeptide amphiphiles was synthesized by tagging a series of cationic oligopeptides with a fluoroalkyl tail via a disulfide spacer. Among the lipopeptide candidates, R6F bearing six arginine moieties and a fluorous tag shows the highest antibacterial activity, and it exhibits an interesting fluorine effect as compared to the non\u2010fluorinated lipopeptides. The high antibacterial activity of R6F is attributed to its excellent bacterial membrane permeability, which further disrupts the respiratory chain redox stress and cell wall biosynthesis of the bacteria. By co\u2010assembling with lipid nanoparticles, R6F showed high therapeutic efficacy and minimal adverse effects in the treatment of MRSA\u2010induced sepsis and chronic wound infection. This work provides a novel strategy to design highly potent antibacterial peptide amphiphiles for the treatment of drug\u2010resistant bacterial infections.<\/jats:p>","DOI":"10.1002\/anie.202403140","type":"journal-article","created":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T15:59:15Z","timestamp":1708703955000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["A Fluorous Peptide Amphiphile with Potent Antimicrobial Activity for the Treatment of MRSA\u2010induced Sepsis and Chronic Wound Infection"],"prefix":"10.1002","volume":"63","author":[{"given":"Jingjing","family":"Hu","sequence":"first","affiliation":[{"name":"Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology School of Life Sciences East China Normal University  Shanghai 200241 China Dongchuan Road, No. 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