Linkage-Directed Regulation of Hyperbranched Polylysines Via α- and ε-Dilysine: Structure−Activity Relationships and Antimicrobial Selectivity

Abstract Hyperbranched polylysine (HPL) is a versatile platform for antimicrobial polymer design, but the relationships among lysine linkage patterns, branching architecture, cationic characteristics, and the balance between antimicrobial activity and cytocompatibility remain unclear. Here α- or ε-dilysine (α-DL or ε-DL) monomers were introduced to predefine local connectivity during thermal polycondensation to tune the linkage composition and branching architecture of HPLs. α-DL increased the fractions of α-linear and dendritic units, whereas ε-DL favored ε-linear units and reduced branching. The ε-DL derived polymers were generally more active against Escherichia coli, Staphylococcus aureus and Candida albicans, with HP(L1-co-εDL1) showing broad spectrum activity and favorable NIH/3T3 fibroblast compatibility. Exploratory multivariate analyses correlated bacterial activity primarily with ζ potential and total amine content, while ε-linkage and branching contributed more prominently to antifungal activity. These findings establish predefined lysine connectivity as a strategy for tuning hyperbranched polylysine linkage composition and branching architecture and balancing antimicrobial potency with mammalian cell compatibility.