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In this study, we developed injectable, covalently cross-linked hydrogels composed of \u03b5-poly-l-lysine (\u03b5-PL) and hyaluronic acid (HA) for localized wound infection treatment. These hydrogels combine the inherent antibacterial properties of \u03b5-PL with the biocompatibility of HA, forming a shear-thinning, self-recovering system suitable for syringe-based administration. We first evaluated the antibacterial activity of pure \u03b5-PL, determining minimum inhibitory and bactericidal concentrations (MIC\/MBC) and evaluating resistance development against ATCC and clinically isolated multidrug-resistant strains (MRSA, ESBL-E. coli, P. aeruginosa). Notably, no resistance emerged in any strain after the serial passages. Hydrogels formed at varying \u03b5-PL\/HA ratios demonstrated strong immediate and long-term bactericidal activity while maintaining high cytocompatibility with murine and human fibroblasts. The hydrogels significantly reduced biofilm formation of S. aureus and MRSA within 24 h, achieving reductions comparable to or greater than vancomycin-gentamicin controls. Rheological analysis confirmed injectability, stability, and tunable stiffness. This study presents the first demonstration that \u03b5-PL-based hydrogels can prevent resistance development in multidrug-resistant pathogens, offering a safe and antibiotic-free approach for infection control. The combination of antibacterial efficacy, resistance prevention, and biocompatibility makes these hydrogels promising candidates for wound infection management.<\/jats:p>","DOI":"10.1021\/acsabm.5c01252","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T23:41:30Z","timestamp":1761867690000},"page":"9916-9930","source":"Crossref","is-referenced-by-count":5,"title":["Injectable \u03b5-Polylysine\/Hyaluronic\nAcid\nHydrogels with Resistance-Preventing Antibacterial Activity for Treating\nWound Infections"],"prefix":"10.1021","volume":"8","author":[{"given":"Artemijs","family":"Sceglovs","sequence":"first","affiliation":[{"name":"Riga Technical University , , Paula Valdena St. 3 , ,","place":["Riga, Latvia, lv-1048"]},{"name":"Headquarters at Riga Technical University , , Paula Valdena St. 3, K-1 , ,","place":["Riga, Latvia, lv-1048"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Siverino","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos , Clavadelerstrasse 8 , ,","place":["Davos, Switzerland, 7270"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingus","family":"Skadins","sequence":"additional","affiliation":[{"name":"Riga Stradins University , , Dzirciema St. 16 ,","place":["Riga, Latvia, lv-1007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Sceglova","sequence":"additional","affiliation":[{"name":"Riga Technical University , , Paula Valdena St. 3 , ,","place":["Riga, Latvia, lv-1048"]},{"name":"Headquarters at Riga Technical University , , Paula Valdena St. 3, K-1 , ,","place":["Riga, Latvia, lv-1048"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valdis","family":"Pirsko","sequence":"additional","affiliation":[{"name":"Riga Stradins University , , Ratsupites St. 5 , ,","place":["Riga, Latvia, lv-1067"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2307-0397","authenticated-orcid":true,"given":"Thomas Fintan","family":"Moriarty","sequence":"additional","affiliation":[{"name":"AO Research Institute Davos , Clavadelerstrasse 8 , ,","place":["Davos, Switzerland, 7270"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juta","family":"Kroica","sequence":"additional","affiliation":[{"name":"Riga Stradins University , , Dzirciema St. 16 ,","place":["Riga, Latvia, lv-1007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9215-0097","authenticated-orcid":true,"given":"Kristine","family":"Salma-Ancane","sequence":"additional","affiliation":[{"name":"Riga Technical University , , Paula Valdena St. 3 , ,","place":["Riga, Latvia, lv-1048"]},{"name":"Headquarters at Riga Technical University , , Paula Valdena St. 3, K-1 , ,","place":["Riga, Latvia, lv-1048"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"2026072914061925200_cit1","unstructured":"7.7 million people die from bacterial infections every year \u2013\n2022 \u2013 ReAct.\n          https:\/\/www.reactgroup.org\/news-and-views\/news-and-opinions\/year-2022\/7-7-million-people-die-from-bacterial-infections-every-year\/ (accessed 2025\u201302\u201319)."},{"key":"2026072914061925200_cit2","unstructured":"WHO updates list\nof drug-resistant bacteria most threatening to human\nhealth.\n          https:\/\/www.who.int\/news\/item\/17-05-2024-who-updates-list-of-drug-resistant-bacteria-most-threatening-to-human-health (accessed 2025\u201306\u201304)."},{"issue":"9","key":"2026072914061925200_cit3","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.3390\/MICROORGANISMS12091920","article-title":"An Overview\nof the Recent Advances in Antimicrobial Resistance","volume":"12","author":"Oliveira","year":"2024","journal-title":"Microorganisms"},{"issue":"4","key":"2026072914061925200_cit4","first-page":"277","article-title":"The Antibiotic\nResistance Crisis: Causes and Threats","volume":"40","author":"Ventola","year":"2015","journal-title":"Pharm.\nTher."},{"key":"2026072914061925200_cit5","unstructured":"Antimicrobial\nresistance.\n          https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/antimicrobial-resistance (accessed 2025\u201306\u201304)."},{"issue":"10459","key":"2026072914061925200_cit6","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/S0140-6736(24)01867-1","article-title":"Global\nburden of bacterial antimicrobial resistance 1990\u20132021: a systematic\nanalysis with forecasts to 2050","volume":"404","author":"Naghavi","year":"2024","journal-title":"Lancet"},{"key":"2026072914061925200_cit7","unstructured":"WHO releases report on state of development of antibacterials. https:\/\/www.who.int\/news\/item\/14-06-2024-who-releases-report-on-state-of-development-of-antibacterials (accessed 2025\u201302\u201319)."},{"key":"2026072914061925200_cit8","unstructured":"WHO outlines 40\nresearch priorities on antimicrobial resistance.\n          https:\/\/www.who.int\/news\/item\/22-06-2023-who-outlines-40-research-priorities-on-antimicrobial-resistance (accessed 2025\u201302\u201319)."},{"key":"2026072914061925200_cit9","unstructured":"Healthcare-associated\ninfections.\n          https:\/\/www.ecdc.europa.eu\/en\/healthcare-associated-infections (accessed 2025\u201306\u201311)."},{"issue":"10","key":"2026072914061925200_cit10","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.1039\/D4BM00155A","article-title":"Multifunctional Antibacterial\nHydrogels for Chronic Wound 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