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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
18 Downloads (Pure)

Abstract

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 (TI = 20.8, TI = 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.

Original languageEnglish
Article number116508
Number of pages22
JournalBiochemical Pharmacology
Volume229
Early online date27 Aug 2024
DOIs
Publication statusPublished - Nov 2024

Keywords

  • Drug resistance
  • Proteolytic tolerance
  • Anti-endotoxin
  • Antimicrobial peptides
  • Peptide modification

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