Cationic Polysaccharide Conjugates as Antibiotic Adjuvants Resensitize Multidrug‐Resistant Bacteria and Prevent Resistance

Abstract In recent years, traditional antibiotic efficacy has rapidly diminished due to the advent of multidrug‐resistant (MDR) bacteria, which poses severe threat to human life and globalized healthcare. 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‐graft‐poly(5‐(1,2‐dithiolan‐3‐yl)‐N‐(2‐guanidinoethyl)pentanamide) (Dex‐g‐PSS_n) is synthesized using disulfide exchange polymerization. Critically, bacterial membranes and efflux pumps are disrupted by a sub‐inhibitory concentration of Dex‐g‐PSS₃₀, which enhances rifampicin (RIF) accumulation inside bacteria and restores its efficacy. Combined Dex‐g‐PSS₃₀ and RIF prevents bacterial resistance in bacteria cultured over 30 generations. Furthermore, Dex‐g‐PSS₃₀ restores RIF effectiveness, reduces inflammatory reactions in a pneumonia‐induced mouse model, and exhibits excellent in vivo biological absorption and degradation capabilities. As an antibiotic adjuvant, Dex‐g‐PSS₃₀ provides a novel resensitizing strategy for RIF against MDR bacteria and bacterial resistance. This Dex‐g‐PSS₃₀ research provides a solid platform for future MDR applications.