Broad-spectrum antibacterial peptidopolysaccharides for targeted therapy of a drug-resistant bacterial liver abscess

Liver abscesses, which are caused primarily by bacteria, represent a significant clinical challenge. Current therapeutic approaches rely heavily on antibiotics, and their efficacy is constrained by the poor drug delivery efficiency and the escalating resistance of bacteria. This study explores a hepatotropic pullulan-based peptidopolysaccharide engineered for liver targeting and broad-spectrum antibacterial activity. With an optimized balance between antibacterial activity and hemocompatibility, copolymer PP11 demonstrated remarkable antibacterial efficacy against all kinds of ESKAPE pathogens, including several important multi-drug resistance (MDR) strains, e.g., vancomycin-resistant Enterococcus faecalis, methicillin-resistant Staphylococcus aureus, tetracycline-resistant and extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-E. coli). Mechanistic studies demonstrated that PP11 is capable of aggregating on bacterial cell membranes and then disrupting membrane integrity. Unlike conventional antibiotics, PP11 showed low susceptibility to induce bacterial resistance owing to this membrane-damaging mechanism. Furthermore, PP11 exhibited pronounced hepatotropic targeting properties both ex vivo and in vivo. The therapeutic efficacy of PP11 was verified in a murine liver abscess model induced by ESBL-E. coli, where it evinced potent bacterial elimination with a log reduction above 3 (> 99.9 % killing) and inflammation-suppressing effects characterized by IL-6 and IL-1β cytokines down-regulation. A four-week animal biosafety study validated that PP11 was non-toxic to major organs (heart, liver, spleen, lungs, and kidneys), particularly unaffected hepatic and renal functions. These results highlight the potential of pullulan-based peptidopolysaccharides as a promising hepatotropic targeting platform, establishing a pioneering exploration for customized antibacterial therapy of hepatic infections. STATEMENT OF SIGNIFICANCE: Liver abscesses pose a pressing clinical concern, especially in the face of rising antibiotic resistance and poor drug delivery efficiency to hepatic tissues. This study introduces a pullulan-based peptidopolysaccharide, PP11, that uniquely combines potent broad-spectrum antibacterial activity (including efficacy against multidrug-resistant (MDR) ESKAPE pathogens) with targeted liver delivery. Unlike conventional antibiotics, PP11 directly disrupts bacterial membranes, minimizing the risk of resistance development. Its selective hepatotropic targeting, demonstrated therapeutic effectiveness in a murine liver abscess model, and favorable safety profile position PP11 as a promising and innovative platform for precision antibacterial therapy in hepatic infections.