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Currently, the development cycle of new antibiotics cannot match the ongoing MDR infection crisis. Therefore, novel strategies are required to resensitize MDR bacteria to existing antibiotics. In this study, novel cationic polysaccharide conjugates Dextran\u2010<jats:italic>graft<\/jats:italic>\u2010poly(5\u2010(1,2\u2010dithiolan\u20103\u2010yl)\u2010<jats:italic>N<\/jats:italic>\u2010(2\u2010guanidinoethyl)pentanamide) (Dex\u2010<jats:italic>g<\/jats:italic>\u2010PSS<jats:italic><jats:sub>n<\/jats:sub><\/jats:italic>) is synthesized using disulfide exchange polymerization. Critically, bacterial membranes and efflux pumps are disrupted by a sub\u2010inhibitory concentration of Dex\u2010<jats:italic>g<\/jats:italic>\u2010PSS<jats:sub>30<\/jats:sub>, which enhances rifampicin (RIF) accumulation inside bacteria and restores its efficacy. Combined Dex\u2010<jats:italic>g<\/jats:italic>\u2010PSS<jats:sub>30<\/jats:sub> and RIF prevents bacterial resistance in bacteria cultured over 30 generations. Furthermore, Dex\u2010<jats:italic>g<\/jats:italic>\u2010PSS<jats:sub>30<\/jats:sub> restores RIF effectiveness, reduces inflammatory reactions in a pneumonia\u2010induced mouse model, and exhibits excellent in vivo biological absorption and degradation capabilities. As an antibiotic adjuvant, Dex\u2010<jats:italic>g<\/jats:italic>\u2010PSS<jats:sub>30<\/jats:sub> provides a novel resensitizing strategy for RIF against MDR bacteria and bacterial resistance. This Dex\u2010<jats:italic>g<\/jats:italic>\u2010PSS<jats:sub>30<\/jats:sub> research provides a solid platform for future MDR applications.<\/jats:p>","DOI":"10.1002\/adma.202204065","type":"journal-article","created":{"date-parts":[[2022,8,13]],"date-time":"2022-08-13T07:06:04Z","timestamp":1660374364000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Cationic Polysaccharide Conjugates as Antibiotic Adjuvants Resensitize Multidrug\u2010Resistant Bacteria and Prevent Resistance"],"prefix":"10.1002","volume":"34","author":[{"given":"Shaowei","family":"Mu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Resource Engineering Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology Ministry of Education) and Laboratory of Biomedical Materials Beijing Advanced Innovation Centre for Soft Matter Science and Engineering Beijing University of Chemical Technology  Beijing 100029 P. 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