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

Abstract

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-K n F m ), onto a thiolated polysaccharide (dextran, Dex) backbone. Their copolymers (Dex-g-K n F m ) 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-K n F m copolymers did not induce drug resistance of MRSA up to 17 passages. In addition, these copolymers have an improved hemocompatibility and exhibit good in vitro biocompatibility with murine myoblast (C2C12) cells. Among the synthesized peptidopolysaccharides, Dex L -g-K 12.5 F 12.5 -50%, as the optimal agent, displayed a selectivity more than 200 times the maximum value of polypeptide molecules. Furthermore, a strong in vivo antimicrobial efficacy with a log reduction above 3 in a mouse bacterial sepsis model has been obtained. These excellent biological properties present a promising prospect for Dexg-K n F m in biomedical applications.

Synthetic Polypeptide Polymers as Simplified Analogues of Antimicrobial Peptides

“…More recently, Chen et al developed a similar strategy based on dextran and copolymers of lysine and phenylalanine. 191 Broad-spectrum antibacterial and antifungal activity were shown for the copolymers, including against multidrug-resistant bacteria. This design decreased the haemolytic activity and exhibited biocompatibility in murine myoblast (C21C12) cells.…”

Mussel-inspired agarose hydrogel scaffolds for skin tissue engineering

“…This study focuses on the design and optimization of agarose-polydopamine composite scaffolds for skin tissue engineering. Agarose is a fascinating polysaccharide due to its controlled self-gelling properties [ [18] , [19] , [20] ]. The formed agarose hydrogels have adjustable mechanical properties and tunable water adsorption capacity, which hold great potentials for various tissue engineering applications.…”

Engineering Biofunctional Enzyme‐Mimics for Catalytic Therapeutics and Diagnostics

“…On the one hand, the modification of Enz‐Ms by functional polymers or biopolymers can improve the biological properties, such as better biocompatibility, targeting effects, and prolonged blood circulation time. [ 232,237 ] On the other hand, the catalytic performances of Enz‐Ms would be influenced by the thickness of the coating and the steric hindrance of macromolecules. [ 51 ]…”