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oai:figshare.com:article/32805737 2026-10-01T16:13:38Z portal_1172 item_type_8 month_year_10_2026

Structure–function relationships and rational optimisation of amphibian skin-derived antimicrobial peptides Yanguo Zhu (24292898) PUREID: 688007531 Antimicrobial peptide rational design biofunctions molecular docking Odorrana grahami Antimicrobial resistance is a major global health threat that demands alternatives to conventional antibiotics. Amphibian skin-derived antimicrobial peptides (AMPs) are promising therapeutic candidates due to their broad-spectrum antimicrobial activity, rapid bactericidal effects, and multifunctional biological properties. However, their clinical application is often limited by insufficient selectivity, cytotoxicity, and incomplete mechanistic understanding.<br><br>This thesis investigated the discovery, optimisation, and mechanistic characterisation of amphibian-derived AMPs using integrated experimental and computational approaches. A novel peptide, QUB-3301, isolated from Odorrana grahami, demonstrated potent antimicrobial activity, particularly against Gram-negative bacteria, with moderate haemolytic toxicity. Rational sequence modification and structure–activity relationship analysis revealed that peptide length, amphipathicity, and stereochemistry critically influenced antimicrobial performance and selectivity. All-atom molecular dynamics simulations further provided atomic-level insight into peptide conformational stability, membrane insertion, and peptide–membrane interactions.<br><br>In parallel, a multifunctional peptide engineering strategy was explored using Senegalin-2. 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> 2026-10-01T16:13:38Z Text Thesis 10.17034/32805737.v1 https://figshare.com/articles/thesis/Structure_function_relationships_and_rational_optimisation_of_amphibian_skin-derived_antimicrobial_peptides/32805737 All Rights Reserved Open Access after 2031-07-31