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Design and Synthesis of Biocompatible, Hemocompatible, and Highly Selective Antimicrobial Cationic Peptidopolysaccharides via Click Chemistry
journal contribution
posted on 2019-05-09, 00:00 authored by Yun Chen, Luofeng Yu, Biao Zhang, Wei Feng, Miao Xu, Lingling Gao, Nian Liu, Qianqian Wang, Xiao Huang, Peng Li, Wei HuangDespite
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 exhibit good in vitro biocompatibility with murine myoblast (C2C12)
cells. Among the synthesized peptidopolysaccharides, DexL-g-K12.5F12.5-50%, 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 Dex-g-KnFm in biomedical applications.
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methicillin-resistant Staphylococcus aureusCandida albicans12.5murine myoblastC 2C cellscationic peptidopolysaccharidesDex LSelective Antimicrobial Cationic PeptidopolysaccharidesK n F m copolymersClick Chemistryselectivityantimicrobial polypeptidesAMPK n F mantimicrobial activitypolypeptide moleculesantifungal activitylog reductioncationic antimicrobial peptidessepsis modeldrug resistanceexhibitGram-negative bacteria17 passagesMRSA200 timesapplicationvivo antimicrobial efficacyPseudomonas aeruginosathiolated polysaccharide
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