Structure–function relationships and rational optimisation of amphibian skin-derived antimicrobial peptides

Fusion with a bradykinin-derived sequence generated Senegalin-2BK, which exhibited enhanced antimicrobial and antibiofilm activities, reduced haemolytic toxicity, and retained smooth muscle bioactivity. Transcriptomic analysis of peptide-treated bladder epithelial cells showed modulation of pathways associated with inflammation, epithelial barrier integrity, and immune signalling, suggesting host-defence–like immunomodulatory potential.<br><br>Additionally, the histamine-releasing peptide Kassinakinin-S was rationally truncated and optimised to generate analogues with improved antimicrobial activity and altered physicochemical properties.

Molecular dynamics simulations demonstrated that truncation reshaped peptide conformation and membrane interaction behaviour.<br><br>Overall, this work establishes a comprehensive structure–function framework for amphibian-derived AMPs by integrating peptide design, bioactivity evaluation, molecular dynamics simulations, and systems-level biological analysis. The findings provide mechanistic insight into peptide–membrane interactions, identify effective optimisation strategies, and support the development of next-generation peptide-based anti-infective therapeutics.<br><br><i>Thesis is embargoed until 31 July 2031.</i>