Posted by Over the past decade, the growing threat of antibiotic resistance has intensified interest in antimicrobial peptides and lipopeptides as promising alternatives to conventional antibiotics due to their lower likelihood of inducing resistance. However, lipopeptides often exhibit undesirable cytotoxicity due to their non-selective membrane-disrupting effects, and their limited aqueous solubility poses a pharmaceutical challenge.
A recent study [1] explores a series of ultrashort cationic lipopeptides (USCLs) composed of a tetrapeptide (L1), derived from buforin II, conjugated with saturated fatty acids of varying chain lengths. The findings reveal that the 16-carbon fatty acid appended lipopeptide (Pal-L1) demonstrates significant antibacterial activity against multidrug-resistant Staphylococcus aureus. However, it also forms heterogeneous aggregates in cell culture medium and exhibits toxicity toward human cells.
To address these limitations, the authors formulated Pal-L1 with randomly methylated α-cyclodextrin (RAMEA) and sulfobutylether-β-cyclodextrin (SBECD), resulting in ultralow-sized molecular dispersion systems that reduce lipopeptide toxicity without compromising antimicrobial efficacy. Using titration ¹H-NMR, 2D NMR spectroscopy, and molecular dynamics simulations, the size, structure, stoichiometry, and dissociation constant of the supramolecular complexes were characterized.
Additionally, interactions between Pal-L1 and neutral or negatively charged model liposomes, in the presence and absence of cyclodextrins, provided insights into membrane selectivity. Based on these findings, a potential mechanism of action for Pal-L1–cyclodextrin complexes on different biological membranes was proposed.
Overall, the study highlights the potential of cyclodextrin formulations to enhance the therapeutic applicability of lipopeptides.
[1] Chiara Bellini, Unai Atxabal, Szilvia Bősze, Orsolya Dobay, Andrea Horváth, Imola Cs. Szigyártó, Tamás Beke-Somfai, Jesús Jiménez-Barbero, István Puskás, Kata Horváti: Supramolecular Complexes of Ultrashort Cationic Lipopeptides with Cyclodextrins: Improved Selectivity and Therapeutic Potential. Aggregate, 2025, e471
First published: 22 January 2025 https://doi.org/10.1002/agt2.741
Image credits: National Institutes of Health (NIH)