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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Development of a novel hybrid antimicrobial peptide for targeted killing of Pseudomonas aeruginosa
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Development of a novel hybrid antimicrobial peptide for targeted killing of Pseudomonas aeruginosa

机译：用于靶向杀灭假单胞菌铜绿假单胞菌的新型杂交抗微生物肽的发展

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The emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa, coupled with shrinking antibiotic pipelines, has increased the demand for new antimicrobials with novel mechanisms of action. As the indiscriminate nature of broad-spectrum antimicrobial toxicity may have negative clinical consequences and increase the incidence of resistance, we have developed a P. aeruginosa-selective antimicrobial peptide capable of preferentially killing P. aeruginosa relative to benign microorganisms. A targeting peptide (PA2) that binds specifically to OprF porin on P. aeruginosa was identified by phage display peptide library screening, and a hybrid peptide was constructed by addition of the targeting peptide to GNU7, a potent antimicrobial peptide. The resulting hybrid peptide PA2-GNU7 exhibited potent antimicrobial activity against P. aeruginosa without causing host toxicity. Confocal laser scanning microscopy analysis and time-kill experiments demonstrated that PA2-GNU7 exhibited a high degree of specificity for P. aeruginosa, and rapidly and selectively killed P. aeruginosa cells in mixed cultures. In addition, in vivo treatment efficacy of PA2-GNU7 was significantly greater than that of conventional antibiotics in a mouse model of MDR P. aeruginosa infection. Taken together, the data suggest that PA2-GNU7 may be a promising template for further development as a novel anti-MDR P. aeruginosa therapeutic agent. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：多药耐药性（MDR）铜绿假单胞菌的出现，加上缩小抗生素管线，增加了对具有新作用机制的抗微生物剂的新的需求。作为广谱抗菌毒性的不加选择的性质可以具有负的临床后果，增加电阻的发生，我们已经开发出能够优先杀死铜绿假单胞菌，相对于良性微生物的铜绿假单胞菌选择性抗微生物肽。靶向肽（PA2）特异性对铜绿假单胞菌OPRF孔蛋白结合的鉴定通过噬菌体展示肽库筛选，和杂合肽通过加入靶向肽GNU7，一种有效的抗微生物肽的构造。将得到的杂合肽PA2-GNU7表现出对铜绿假单胞菌的抗菌活性，而不会引起宿主毒性。共聚焦激光扫描显微镜分析和时间 - 杀菌实验证实，PA2-GNU7表现出对铜绿假单胞菌高度特异性的，并迅速且选择性地杀死铜绿假单胞菌细胞在混合培养物。此外，PA2-GNU7的体内治疗效果比在MDR铜绿假单胞菌感染的小鼠模型中常规抗生素显著更大。总之，数据表明，PA2-GNU7可用于进一步开发作为一种新的抗MDR铜绿假单胞菌治疗剂的有前途的模板。 （c）2019年Elsevier Masson SAS。版权所有。

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