Heterofunctional Cationic Polyester Dendrimers as Antibacterial Agents: The Role of Internal and External Charges

Antimicrobial resistance is a global health crisis, necessitating novel antibacterial strategies. Polycations, particularly polyester dendrimers, are promising due to their structural precision and membrane-disruptive mechanisms. However, existing dendrimers lack versatility in charge distribution, limiting their antibacterial efficacy. Here, we report two families of cationic polyester dendrimers (up to the third generation) with either internal or combined internal and external charges compared with traditional bis-MPA dendrimers bearing only external cations. These heterofunctional dendrimers, built from AB₂C monomers, carry up to 45 charges at the highest generation. Internal propargyl amines were introduced via CuAAC chemistry, while external β-alanine provided complementary charges in the second family. Dendrimers with both internal and external charges showed superior antibacterial activity against Gram-positive and Gram-negative bacteria while maintaining biocompatibility. The second-generation dendrimer (G2-(PA-NH₃⁺)₉-(β-Ala-NH₃⁺)₁₂) exhibited bacteriostatic and bactericidal activity at 10-21 μM and enhanced Escherichia coli sensitivity, with favorable biodegradation, highlighting their promise as antimicrobials where charge distribution is key for efficacy.