Aryl-Alkyl-Lysines Interact with Anionic Lipid Components of Bacterial Cell Envelope Eliciting Anti-Inflammatory and Antibiofilm Properties

[Image: see text] The emergence of bacterial resistance and hesitance in approving new drugs has bolstered research on membrane-active agents such as antimicrobial peptides and their synthetic derivatives as therapeutic alternatives against bacterial infections. Herein, we document the action of aryl-alkyl-lysines on liposomes mimicking bacterial membranes using solid-state nuclear magnetic resonance spectroscopy. A significant perturbation of the lipid thickness and order parameter of the lipid membrane was observed upon treatment with this class of compounds. Encouraged by these results, the ability of the most active compound (NCK-10) to interact with aggregates of lipopolysaccharides (LPSs) was studied. In vitro experiments showed that NCK-10 was able to prevent the LPS-induced stimulation of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The compound could also disrupt the biofilms of Pseudomonas aeruginosa in vitro and bring down the bacterial burden by more than 99% in a mice model of burn infections caused by the biofilms of P. aeruginosa.