Optimisation and mechanistic studies of antimicrobial peptides derived from the skin secretion of the Australian green tree frog (Litoria caerulea)

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>