Investigations into the membrane activity of arenicin antimicrobial peptide AA139

Arenicin-3 is an amphipathic beta-hairpin antimicrobial peptide that is produced by the lugworm Arenicola marina. In this study, we have investigated the mechanism of action of arenicin-3 and an optimized synthetic analogue, AA139, by studying their effects on lipid bilayer model membranes and Escherichia coli bacterial cells. The results show that simple amino acid changes can lead to subtle variations in their interaction with membranes and therefore alter their pre-clinical potency, selectivity and toxicity. While the mechanism of action of arenicin-3 is primarily dependent on universal membrane permeabilization, our data suggest that the analogue AA139 relies on more specific binding and insertion properties to elicit its improved antibacterial activity and lower toxicity, as exemplified by greater selectivity between lipid composition when inserting into model membranes i.e. the N-terminus of AA139 seems to insert deeper into lipid bilayers than arenicin-3 does, with a clear distinction between zwitterionic and negatively charged lipid bilayer vesicles, and AA139 demonstrates a cytoplasmic permeabilization dose response profile that is consistent with its greater antibacterial potency against E. coli cells compared to arenicin-3.

Automated summary

In this study, the mechanism of action of arenicin-3 and its synthetic analogue AA139 were investigated. The results showed that simple amino acid changes can affect their interaction with membranes, leading to changes in their potency, selectivity, and toxicity. AA139 demonstrated improved antibacterial activity and lower toxicity compared to arenicin-3, possibly due to its specific binding and insertion properties.