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Antimicrobial peptides (AMPs) offer broad\u2010spectrum activity, yet most fail in clinical translation due to known limitations. Here, TPL6 is developed, a TP4\u2010derived AMP with glycine\u2010rich segments deleted, yielding a variant with potent, robust antimicrobial activity and reduced cytotoxicity. TPL6 retains its \u03b1\u2010helical structure and activity under high glucose and salt, and after heat stress. It also does not induce microbial resistance after prolonged exposure. Formulated with adjuvants into a hydrogel, TPL6 gel restores activity in serum\u2010rich environments and outperforms Bacineocin ointment in simulated wound fluid. The gel further prevents formation and eradicates biofilms of multidrug\u2010resistant (MDR) pathogens. In\n                    <jats:italic>ex vivo<\/jats:italic>\n                    porcine skin and diabetic mouse wound models infected with MDR\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    or\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    , TPL6 gel shows superior therapeutic efficacy versus Bacineocin ointment and Canesten 1% cream. Thus, this study shows that structural modification and adjuvant\u2010based formulation of TPL6 can overcome key translational barriers that have hindered clinical application of AMPs, supporting its potential as an antibiotic\u2010free treatment for drug\u2010resistant wound infections.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202503863","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T07:44:12Z","timestamp":1763797452000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Optimized TPL6 Peptide Gel Exhibits Broad\u2010Spectrum Antimicrobial Activity and Effectively Treats Drug\u2010Resistant Wound Infections in Diabetic Mice"],"prefix":"10.1002","volume":"15","author":[{"given":"Wen\u2010Chun","family":"Lin","sequence":"first","affiliation":[{"name":"Marine Research Station Institute of Cellular and Organismic Biology Academia Sinica  Jiaushi Ilan 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