A molecular architectural design that promises potent antimicrobial activity against multidrugresistant pathogens
A molecular architectural design that promises potent antimicrobial activity against multidrugresistant pathogens
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一种分子结构设计，有望对多重耐药病原体发挥有效的抗菌活性
DOI：
10.1038/s41427-021-00287-y
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发表时间：
2021
影响因子：
9.7
通讯作者：
Zhenhui Kang
中科院分区：
文献类型：
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作者：
Bing Yuan;Jiaojiao Liu;Zhixiong Deng;Lin Wei;Wenwen Li;Yujiang Dou;Zhonglan Chen;Che Zhang;Yu Xia;Jing Wang;Mengling Zhang;Kai Yang;Yuqiang Ma;Zhenhui Kang
解决耐药病原体的毁灭性威胁需要发现具有先进作用机制和/或药物设计新策略的新抗生素。在此，从生物物理学的角度来看，我们设计了一类合成的抗菌复合物，具有专门的架构的基础上蜂毒肽（梅尔），天然抗菌肽，和聚（乙二醇）（PEG），临床上可用的代理，作为积木，显示出强大的和结构调节的抗菌活性。在这些复合物中，由一个末端连接有长链PEG（例如，与原始Mel相比，PEG 12 k-1*Mel）表现出最显著的性能改善，抗菌效率提高高达500%，对多药耐药病原体具有优异的体外活性（在2-32 µg mL−1的最小抑制浓度范围内），体外细胞毒性降低68%，体内急性毒性降低57%。描述了在膜识别中的脂质特异性作用模式和在复合物的细菌膜穿孔中的加速“通道”效应。我们的研究结果介绍了一种新的方法来设计高效和低毒性的抗菌药物的基础上的建筑调制与临床可用的代理。
Addressing the devastating threat of drug-resistant pathogens requires the discovery of new antibiotics with advanced action mechanisms and/or novel strategies for drug design. Herein, from a biophysical perspective, we design a class of synthetic antibacterial complexes with specialized architectures based on melittin (Mel), a natural antimicrobial peptide, and poly(ethylene glycol) (PEG), a clinically available agent, as building blocks that show potent and architecture-modulated antibacterial activity. Among the complexes, the flexibly linear complex consisting of one Mel terminally connected with a long-chained PEG (e.g., PEG12k–1*Mel) shows the most pronounced improvement in performance compared with pristine Mel, with up to 500% improvement in antimicrobial efficiency, excellent in vitro activity against multidrug-resistant pathogens (over a range of minimal inhibitory concentrations of 2–32 µg mL−1), a 68% decrease in in vitro cytotoxicity, and a 57% decrease in in vivo acute toxicity. A lipid-specific mode of action in membrane recognition and an accelerated “channel” effect in perforating the bacterial membrane of the complex are described. Our results introduce a new way to design highly efficient and low-toxicity antimicrobial drugs based on architectural modulations with clinically available agents.