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We report the rational design of a small molecule TPL(II)\u201007, that combines multiple functional modules: (i) 2\u2010phenylthiophene for specific recognition and binding to lipid II, a key intermediate in peptidoglycan biosynthesis; (ii) an adamantane fragment with high interfacial permeability to destabilize lipid packing; (iii) a cationic lysine moiety to disperse biofilms; and (iv) a moderate aliphatic chain to disrupt membrane integrity. Among seven analogues, TPL(II)\u201007 exhibited the highest potency, highlighting the synergistic contribution of each component. Mechanistic assays confirmed preferential binding of lipid II, bactericidal potency, biofilm dispersion, and the generation of reactive oxygen species, effective against both drug\u2010resistant (MIC 19\u00a0\u00b5M) and drug\u2010sensitive (MIC 9\u00a0\u00b5M)\n                    <jats:italic>S. aureus<\/jats:italic>\n                    strains. TPL(II)\u201007 demonstrated excellent biocompatibility, with IC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0&gt;\u00a050\u00a0mM in HEK\u2010293 and WI38 cells and negligible hemolytic activity. In addition, it suppressed key virulence traits, including hemolysin activity, biofilm formation, and staphyloxanthin production. Further, a borate\u2010functionalized guar gum hydrogel incorporating TPL(II)\u201007 achieved effective infection control and enhanced wound repair in a murine excisional model, establishing thiophene\u2010based lipid II targeting as a versatile platform for next\u2010generation antimicrobials with dual antibacterial and wound\u2010healing potential.\n                  <\/jats:p>","DOI":"10.1002\/anie.5919230","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:09:40Z","timestamp":1781158180000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thiophene\u2010Engineered Lipid II Recognition Enables Potent Membranolytic Eradication of MRSA"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4379-8417","authenticated-orcid":false,"given":"Aniket","family":"Jana","sequence":"first","affiliation":[{"name":"Smart Healthcare Interdisciplinary Research 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