Coagulation factors VII, IX and X are effective antibacterial proteins against drug-resistant Gram-negative bacteria
Coagulation factors VII, IX and X are effective antibacterial proteins against drug-resistant Gram-negative bacteria
复制标题
凝血因子 VII、IX 和 X 是针对耐药革兰氏阴性菌的有效抗菌蛋白
DOI：
10.1038/s41422-019-0202-3
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发表时间：
2019-09-01
期刊：
影响因子：
44.1
通讯作者：
Song, Xu
中科院分区：
文献类型：
--
作者：
Chen, Jinwu;Li, Xiaojie;Song, Xu
由于缺乏有效药物，耐药“超级细菌”引起的感染对公共卫生构成了紧迫的威胁;然而，某些具有内在抗菌活性的哺乳动物蛋白质可能被低估。在这里，我们揭示了因子VII，IX和X对革兰氏阴性菌的抗菌特性，这三种蛋白质在凝血级联反应的启动中具有公认的作用。这些因子通过其轻链（LC）发挥抗菌功能。与靶向细胞代谢或细胞质膜的许多抗菌剂不同，LC通过水解细菌外膜的主要组分脂多糖起作用，脂多糖对革兰氏阴性菌的存活至关重要。因子VII的LC在纳摩尔浓度下对所有测试的革兰氏阴性细菌（包括广泛耐药（XDR）病原体）表现出体外功效。在体内对抗XDR铜绿假单胞菌和鲍氏不动杆菌感染也非常有效。本研究通过对因子VII、IX和X作为抗菌蛋白的独特作用机制的解读，进一步加深了我们对凝血系统在宿主防御中作用的认识，并提示这些因子可能通过其凝血和抗感染的双重功能参与了凝血障碍相关疾病如败血症的发病机制。此外，这项研究可能为对抗革兰氏阴性“超级细菌”提供新的策略。
Infections caused by drug-resistant "superbugs" pose an urgent public health threat due to the lack of effective drugs; however, certain mammalian proteins with intrinsic antibacterial activity might be underappreciated. Here, we reveal an antibacterial property against Gram-negative bacteria for factors VII, IX and X, three proteins with well-established roles in initiation of the coagulation cascade. These factors exert antibacterial function via their light chains (LCs). Unlike many antibacterial agents that target cell metabolism or the cytoplasmic membrane, the LCs act by hydrolyzing the major components of bacterial outer membrane, lipopolysaccharides, which are crucial for the survival of Gram-negative bacteria. The LC of factor VII exhibits in vitro efficacy towards all Gram-negative bacteria tested, including extensively drug-resistant (XDR) pathogens, at nanomolar concentrations. It is also highly effective in combating XDR Pseudomonas aeruginosa and Acinetobacter baumannii infections in vivo. Through decoding a unique mechanism whereby factors VII, IX and X behave as antimicrobial proteins, this study advances our understanding of the coagulation system in host defense, and suggests that these factors may participate in the pathogenesis of coagulation disorder-related diseases such as sepsis via their dual functions in blood coagulation and resistance to infection. Furthermore, this study may offer new strategies for combating Gram-negative "superbugs".