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Optimisation and mechanistic studies of antimicrobial peptides derived from the skin secretion of the Australian green tree frog (Litoria caerulea) Wudi Wang (24292889) PUREID: 687882046 Antimicrobial peptides frog skin secretion drug resistance biofunctions cancer Caerin Caeridin With the widespread misuse of antibiotics, drug resistance has become a persistent challenge in clinical treatments. As a class of natural products, antimicrobial peptides (AMPs) have garnered increasing attention for their potential to address this issue. QUB-2618, Caerin 3.5, and Caeridin 2 are AMPs derived from the skin secretions of the Australian green tree frog, Litoria caerulea. Their biological activities were assessed through antibacterial assays, biofilm inhibition assays, bactericidal kinetics studies, anti-proliferation assays, and trypan blue exclusion tests. In addition, their cytotoxicity was evaluated using horse erythrocytes and human keratinocytes.<br>Among the three peptides, QUB-2618 exhibited broad-spectrum antibacterial and promising anticancer activity, albeit with significant cytotoxicity. In contrast, Caerin 3.5 and Caeridin 2 demonstrated minimal biological activity. To optimize these peptides, two modification strategies were employed: increasing net positive charge to enhance antimicrobial activity and reducing hydrophobicity to decrease cytotoxicity. Furthermore, alanine scanning was conducted on QUB-2618 to identify residues with minimal impact on bioactivity. Substitutions at positions 7, 8, 15, 20, and 23 were found to lower cytotoxicity without compromising activity and were selected for modification. Notably, modified versions of Caerin 3.5 and Caeridin 2 showed improved bioactivity compared to their parent peptides. However, further derivatives such as K4-19-3.5 and CD2+5K, while exhibiting increased net charge, did not enhance bioactivity and instead elevated cytotoxicity. This suggests that the electrostatic attraction between the peptide and bacterial membranes may reach a saturation point, beyond which increased charge primarily affects mammalian cell membranes, thereby raising cytotoxicity. In conclusion, QUB-2618, Caerin 3.5, and Caeridin 2 represent promising AMP candidates.<br><br><i>Thesis is embargoed until 31 July 2031.</i><br> 2026-10-01T16:13:50Z Text Thesis 10.17034/32805713.v1 https://figshare.com/articles/thesis/Optimisation_and_mechanistic_studies_of_antimicrobial_peptides_derived_from_the_skin_secretion_of_the_Australian_green_tree_frog_Litoria_caerulea_/32805713 All Rights Reserved Open Access after 2031-07-31