Supramolecular Complexes of Ultrashort Cationic Lipopeptides with Cyclodextrins: Improved Selectivity and Therapeutic Potential

ABSTRACT In the last decade, the rise of antibiotic resistance has heightened interest in antimicrobial peptides and lipopeptides as promising alternatives to conventional antibiotics because of their lower propensity to develop resistance. However, lipopeptides often show undesired cytotoxicity due to their non‐selective membrane disruptive effect, and their limited aqueous solubility represents a matter of concern from a pharmaceutical point of view. This study demonstrates a panel of ultrashort cationic lipopeptides (USCLs) consisting of a tetrapeptide (L1), originated from buforin II, coupled with saturated fatty acids of different lengths. Our results highlight that the 16‐carbon fatty acid lipopeptide (Pal‐L1) exhibits relevant antibacterial activity against multiresistant Staphylococcus aureus strain. However, the formation of heterogenic aggregates in cell culture medium and toxic effects on human cells were also observed. Pal‐L1 formulation with the randomly methylated α‐cyclodextrin (RAMEA) and the sulfobutylether‐β‐cyclodextrin (SBECD) has resulted in a production of ultralow‐sized molecular dispersion systems and reduced lipopeptide toxicity without compromising its antimicrobial activity. With titration 1 H‐NMR, 2D NMR experiments, together with molecular dynamics simulations, we described the size, structure, stoichiometry, and dissociation constant of the supramolecular complexes. Interactions of neutral and negatively charged model liposomes with Pal‐L1 lipopeptide in the presence or absence of cyclodextrins serve an explanation for the membrane selectivity, and based on the results, we proposed a potential mechanism of action for the Pal‐L1+cyclodextrin complexes on different biological membranes. Overall, our model characterization points out that cyclodextrin formulation improves the therapeutical applicability of lipopeptides.