The acute need for the development of new drugs replacing obsolete antibiotics pushes scientists to not only discover new molecules and make them therapeutically valuable but to also investigate their mechanisms of action. Antimicrobial peptides (AMPs) generally have a set of common features, including being cationic and amphipathic, which allows them to possess a broad range of antibacterial activity. However, the variety of mechanisms of action employed by AMPs is tremendous and most molecules do not limit themselves to one single mechanism of action but rather utilise multiple, rendering the peptide class unique.
Arenicin-3 is a 21 amino acid AMP belonging to the arenicin peptide family, produced by the lugworm, Arenicola marina. It possess a β-hairpin fold supported by two disulfide bonds. Arenicin-3 and its analogs exhibit potent antimicrobial activity in vitro against a broad range of multi-resistant pathogenic Gram-negative bacteria. The peptide also demonstrates in vivo activity in urinary tract infection and pneumonia E. coli mouse models. However, despite being potent, arenicin-3 displays high toxicity against mammalian cells and therefore results in inapplicability as a drug candidate.
In this study, we aim to investigate the interaction of arenicin peptides with lipid model membrane by NMR. Typically such study is performed in detergent micelles. However, this model is not representative of the phospholipid bilayer complexity of native bacterial or mammalian cells membrane. Thus in our study we aim to use nanodiscs as a lipid bilayer model membrane. By following the titration experiment between arenicin peptide and nanodiscs, we aim to get an insight into the key amino acid/s involved in the binding interaction between arenicin peptide with the lipid membrane. Such data will therefore have a high impact on the understanding of the mode of action of arenicin peptide and thus the design of therapeutically improved analogs.