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The recent emergence of highly fatal infections, caused by carbapenem-resistant PA, has called for novel antimicrobial therapies and strategies. In this study, we highlight the therapeutic potential of \u03b5-poly-L-lysine (\u03b5PL), an antimicrobial polymer for treating extensively-and pan-drug-resistant-PA. \u03b5PL displayed potent antimicrobial activity against all eight drug-resistant PA, including carbapenem- and polymyxin-resistant PA. It exhibited a low risk of AMR evolution, with no evidence of cross-resistance with polymyxin B (a last-line treatment for drug-resistant Gram-negative bacteria). We further demonstrated promising in vivo efficacy and safety of \u03b5PL against PA in a pre-clinical PA keratitis model, with comparable effects to topical levofloxacin (a gold standard treatment of infectious keratitis) in terms of clinical scoring, corneal health\/thickness, and bacterial bioburden. In view of its broad-spectrum antimicrobial activity, low risk of AMR evolution and cross-resistance with existing last-line antibiotics, and general acceptance of safety when orally administered, \u03b5PL serves as a promising novel antimicrobial agent for further clinical development and translation to tackle antimicrobial resistance.<\/jats:p>","DOI":"10.1038\/s44259-025-00142-y","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T11:00:23Z","timestamp":1757415623000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Biosynthetic \u03b5-poly-L-lysine for the treatment of extensively- and pan-drug-resistant Pseudomonas aeruginosa"],"prefix":"10.1038","volume":"3","author":[{"given":"Darren Shu Jeng","family":"Ting","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thet Tun","family":"Aung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatesh","family":"Mayandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercy Halleluyah","family":"Periayah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice Tze Leng","family":"Goh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugil","family":"Muthu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veluchamy Amutha","family":"Barathi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodhbir S.","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald Tiang Hwee","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajamani","family":"Lakshminarayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"142_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanmic.2024.07.010","volume":"6","author":"CS Ho","year":"2025","unstructured":"Ho, C. 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