Antimicrobial activities and action mechanism studies of transportan 10 and its analogues against multidrug-resistant bacteria
Antimicrobial activities and action mechanism studies of transportan 10 and its analogues against multidrug-resistant bacteria
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Transportan 10及其类似物对多重耐药菌的抗菌活性及作用机制研究
DOI：
10.1002/psc.2781
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发表时间：
2015
影响因子：
2.1
通讯作者：
Wang Rui
中科院分区：
文献类型：
--
作者：
Xie Junqiu;Gou Yuanmei;Zhao Qian;Li Sisi;Zhang Wei;Song Jingjing;Mou Lingyun;Li Jingyi;Wang Kairong;Zhang Bangzhi;Yang Wenle;Wang Rui
多药耐药细菌的增加被认为是一个严重的公共卫生威胁，迫切需要开发新型抗菌剂。已发现与抗微生物肽具有共同特征的细胞穿透肽具有抗微生物活性，目前被认为是抗生素的潜在替代品。Transportan 10是一种嵌合细胞穿透肽，据报道可将生物相关货物转运到哺乳动物细胞中并对微生物膜造成损伤。在本研究中，我们设计了一系列TP10类似物，并研究了它们的构效关系。我们首先评估了这些化合物对多重耐药细菌的抗菌活性，这些细菌是大多数医院感染的原因。我们的研究结果表明，这些化合物中有几种具有有效的抗微生物和生物膜抑制活性。我们还测量了这些化合物的毒性，发现赖氨酸取代可以增加抗菌活性，但显着增强细胞毒性。Pro的引入可以降低细胞毒性，但破坏了螺旋结构，导致活性丧失。在机制研究中，TP10通过膜活性和DNA结合活性杀死细菌。总之，TP10及其类似物可以开发成为治疗多重耐药细菌引起的感染的有希望的抗生素候选物。版权所有© 2015欧洲肽协会和约翰威利父子有限公司。
The increased emergence of multidrug‐resistant bacteria is perceived as a critical public health threat, creating an urgent need for the development of novel classes of antimicrobials. Cell‐penetrating peptides that share common features with antimicrobial peptides have been found to have antimicrobial activity and are currently being considered as potential alternatives to antibiotics. Transportan 10 is a chimeric cell‐penetrating peptide that has been reported to transport biologically relevant cargoes into mammalian cells and cause damage to microbial membranes. In this study, we designed a series of TP10 analogues and studied their structure‐activity relationships. We first evaluated the antimicrobial activities of these compounds against multidrug‐resistant bacteria, which are responsible for most nosocomial infections. Our results showed that several of these compounds had potent antimicrobial and biofilm‐inhibiting activities. We also measured the toxicity of these compounds, finding that Lys substitution could increase the antimicrobial activity but significantly enhanced the cytotoxicity. Pro introduction could reduce the cytotoxicity but disrupted the helical structure, resulting in a loss of activity. In the mechanistic studies, TP10 killed bacteria by membrane‐active and DNA‐binding activities. In conclusion, TP10 and its analogues could be developed into promising antibiotic candidates for the treatment of infections caused by multidrug‐resistant bacteria. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.