Functional characterisation and modification of a novel Kunitzin peptide for use as an anti-trypsin antimicrobial peptide against drug-resistant Escherichia coli

文献类型： 外文期刊

第一作者： Wang, Zhizhong

作者： Wang, Zhizhong;Ding, Wenjing;Chen, Xiaoling;Ma, Chengbang;Jiang, Yangyang;Wang, Tao;Chen, Tianbao;Shaw, Chris;Wang, Lei;Zhou, Mei;Shi, Daning

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关键词： Antimicrobial peptides; Drug resistance; Proteolytic tolerance; Peptide modification; Anti-endotoxin

期刊名称：BIOCHEMICAL PHARMACOLOGY （ 影响因子：5.6； 五年影响因子：5.7 ）

ISSN： 0006-2952

年卷期： 2024 年 229 卷

页码：

收录情况： SCI

摘要： In recent decades, antimicrobial peptides (AMPs) have emerged as highly promising candidates for the next generation of antibiotic agents, garnering significant attention. Although their potent antimicrobial activities and ability to combat drug resistance make them stand out among alternative agents, their poor stability has presented a great challenge for further development. In this work, we report a novel Kunitzin AMP, Kunitzin-OL, from the frog Odorrana lividia, exhibiting dual antimicrobial and anti-trypsin activities. Through functional screening and comparison with previously reported Kunitzin peptides, we serendipitously discovered a unique motif (-KVKF-) and unveiled its crucial role in the antibacterial functions of Kunitzin-OL by modifying it through motif removal and duplication. Among the designed derivatives, peptides 4 and 8 demonstrated remarkable antimicrobial activities and low cytotoxicity, with high therapeutic index (TI) values (TI4 = 20.8, TI8 = 20.8). Furthermore, they showed potent antibacterial efficacy against drug-resistant Escherichia coli strains and exhibited lipopolysaccharide (LPS)-neutralising activity, effectively alleviating LPS-induced inflammatory responses. Overall, our findings provide a new short motif for designing effective AMP drugs and highlight the potential of the Kunitztin trypsin inhibitory loop as a valuable motif for the design of AMPs with enhancing proteolytic stability.

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