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    PEGylation enhances the antibacterial and therapeutic potential of amphibian host defence peptides

    Year: 2022

    Journal: Biochim. Biophys. Acta-Biomembr., Volume 1864, FEB 1

    Authors: Dennison, Sarah R.; Reddy, Subrayal M.; Morton, Leslie H. G.; Harris, Frederick; Badiani, Kamal; Phoenix, David A.

    Keywords: Aureins; C-terminal PEGylation; alpha-Helical; Amphiphilic; Membrane interactions; Haemolysis; Circular dichroism; Langmuir Blodgett monolayers

    Aurein 2.1, aurein 2.6 and aurein 3.1 are amphibian host defence peptides that kill bacteria via the use of lytic amphiphilic alpha-helical structures. The C-terminal PEGylation of these peptides led to decreased antibacterial activity (Minimum Lethal Concentration (MLCs) down arrow circa one and a half to threefold), reduced levels of amphiphilic alpha-helical structure in solvents (alpha-helicity down arrow circa 15.0%) and lower surface activity (Delta pi down arrow > 1.5 mN m(-1)). This PEGylation of aureins also led to decreased levels of amphiphilic alpha-helical structure in the presence of anionic membranes and zwitterionic membranes (alpha-helicity down arrow > 10.0%) as well as reduced levels of penetration (Delta pi down arrow > 3.0 mN m(-1)) and lysis (lysis down arrow > 10.0%) of these membranes. Based on these data, it was proposed that the antibacterial action of PEGylated aureins involved the adoption of alpha-helical structures that promote the lysis of bacterial membranes, but with lower efficacy than their native counterparts. However, PEGylation also reduced the haemolytic activity of native aureins to negligible levels (haemolysis down arrow from circa 10% to 3% or less) and improved their relative therapeutic indices (RTIs up arrow circa three to sixfold). Based on these data, it is proposed that PEGylated aureins possess the potential for therapeutic development; for example, to combat infections due to multi-drug resistant strains of S. aureus, designated as high priority by the World Health Organization.
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