Design and Synthesis of Biocompatible, Hemocompatible, and Highly Selective Antimicrobial Cationic Peptidopolysaccharides via Click Chemistry

Despite the excellent antimicrobial activity, the high toxicity and low selectivity of cationic antimicrobial peptides (AMPs) and their synthetic analogues impede their biomedical applications. In this study, we report a series of cationic peptidopolysaccharides synthesized by thiol–ene click chemistry of grafting antimicrobial polypeptides, methacrylate-ended poly(lysine-random-phenylalanine) (Me-KnFm), onto a thiolated polysaccharide (dextran, Dex) backbone. Their copolymers (Dex-g-KnFm) exhibit potent broad-spectrum antibacterial and antifungal activity against Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), Gram-positive bacteria [methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis], and fungi (Candida albicans) with minimal inhibitory concentrations in the range of 31.25–500 μg·mL–1. More importantly, Dex-g-KnFm copolymers did not induce drug resistance of MRSA up to 17 passages. In addition, these copolymers have an improved hemocompatibility and e...