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Sci Rep:農科院飼料所王建華研究組創制新型抗生素替代品

2017年3月13日, 國際學術權威刊物自然出版集團旗下子刊《Scientific Reports》雜誌線上發表了中國農業科學院飼料研究所王建華研究組的一篇研究論文, 論文報導了團隊成功創制新型抗生素替代品——新型抗菌抗內毒素雙效肽, 其安全性高、抗菌性更強, 並可解內毒素, 具有很好的新藥臨床化開發優勢。 團隊研究助理郝婭為論文第一作者, 團隊王秀敏和王建華為並列通訊作者。

抗生素耐藥性、藥物殘留及近年出現的“超級細菌”為抗生素類藥物的使用敲響警鐘, 治療過程中又存在副作用——革蘭氏陰性病原菌內毒素脂多糖(LPS)釋放,

直接威脅機體健康, 因此開發新型抗生素替代品迫在眉睫。 目前, 在食品醫藥及飼料獸藥行業具有廣泛應用潛力的抗生素替代品——牛乳鐵蛋白衍生肽, 雖具有廣譜殺菌性, 但存在溶血性較高, 生物安全性低的問題。

科研團隊利用多氨基酸組合定點突變技術, 從核心抗菌序列入手, 對牛乳鐵蛋白衍生肽3個關鍵位點進行替換, 篩選出的2條突變體比母體肽具更強的抗金黃色葡萄球菌、耐甲氧西林金黃色葡萄球菌(MRSA)、沙門氏菌活性, 且溶血性更低。 研究還發現突變體抑制病原菌去氧核糖核酸(DNA)、核糖核酸(RNA)和蛋白質合成的能力更強。 動物實驗顯示, 染菌小鼠注射10-15 mg/kg可在10小時內顯著降低體內病原菌量。 此外, 突變體可結合細菌內毒素,

通過降低小鼠血清促炎因數水準抑制炎症產生, 減少內毒素對小鼠肺部的誘導損傷, 顯著提高因內毒素引發毒血症的小鼠存活率。

原文連結:

原文摘要:

Bovine lactoferricin (LfcinB) has potent antibacterial, antifungal and antiparasitic activities but is also hemolytic. Our objective was to identify LfcinB17-31 derivatives with reduced hemolysis and improved antimicrobial activity via substituting Cys3, Arg4, Gln7, Met10, and Gly14 with more hydrophobic residues. Two peptides, Lfcin4 and Lfcin5, showed higher activity against Staphylococcus aureus and Salmonella enteritidis and lower hemolytic activity than the parent peptide LfcinB17-31. These peptides permeabilized the outer and inner membranes of S. enteritidis; however, Lfcin5 did not permeabilize the inner membrane of S. aureus. Gel retardation and circular dichroism spectra showed that Lfcin4 and Lfcin5 bound to bacterial genomic DNA. Lfcin4 inhibited DNA, RNA and protein synthesis. Both peptides induced the peeling of membranes and the lysis of S. enteritidis. At doses of 10 and 15 mg/kg, Lfcin4 and Lfcin5 reduced the bacterial counts in infected thigh muscles by 0.03‒0.10 and 0.05‒0.63 log10 CFU/g of tissue, respectively, within 10 h. Lfcin4 and Lfcin5 enhanced the survival rate of endotoxemic mice; reduced serum IL-6, IL-1β and TNF-α levels; and protected mice from lipopolysaccharide-induced lung injury. These data suggest that Lfcin4 and Lfcin5 may be antimicrobial and anti-endotoxin peptides that could serve as the basis for the development of dual-function agents.

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