Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) , Nanjing Tech University , Nanjing 211816 , P. R. China.
Xi'an Institute of Flexible Electronics (IFE) & Xi'an Institute of Biomedical Materials and Engineering (IBME) , Northwestern Polytechnical University (NPU) , 127 West Youyi Road , Xi'an 710072 , P. R. China.
Biomacromolecules. 2019 Jun 10;20(6):2230-2240. doi: 10.1021/acs.biomac.9b00179. Epub 2019 May 22.
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 F ), onto a thiolated polysaccharide (dextran, Dex) backbone. Their copolymers (Dex- g-K F ) 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. More importantly, Dex- g-K F 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- g-KF-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-K F in biomedical applications.
尽管阳离子抗菌肽 (AMPs) 及其合成类似物具有优异的抗菌活性，但它们的高毒性和低选择性阻碍了它们在生物医学中的应用。在这项研究中，我们报告了一系列通过硫醇-烯点击化学接枝抗菌多肽、甲基丙烯酰基封端的聚（赖氨酸-随机-苯丙氨酸）（Me-K F ）到巯基化多糖（葡聚糖，Dex）主链上合成的阳离子糖肽。它们的共聚物（Dex-g-K F ）对革兰氏阴性菌（铜绿假单胞菌和大肠杆菌）、革兰氏阳性菌（耐甲氧西林金黄色葡萄球菌（MRSA）和表皮葡萄球菌）和真菌（白色念珠菌）具有广谱抗菌和抗真菌活性，最小抑菌浓度范围为 31.25-500μg·mL。更重要的是，Dex-g-K F 共聚物在 17 次传代中不会诱导 MRSA 产生耐药性。此外，这些共聚物具有改善的血液相容性，并表现出良好的体外生物相容性与小鼠成肌细胞（C2C12）细胞。在所合成的糖肽中，作为最佳试剂的 Dex-g-KF-50% 对革兰氏阳性菌的选择性超过多肽分子的最大值 200 倍以上。此外，在小鼠细菌性败血症模型中获得了超过 3 个对数减少的强大体内抗菌疗效。这些优异的生物学特性为 Dex-g-K F 在生物医学中的应用提供了广阔的前景。
