The antimicrobial fibupeptide lugdunin forms water-filled channel structures in lipid membranes

• Published in: Nature communications 2024-04, Vol.15 (1), p.3521-3521, Article 3521
• Main Authors: Ruppelt, Dominik, Trollmann, Marius F. W., Dema, Taulant, Wirtz, Sebastian N., Flegel, Hendrik, Mönnikes, Sophia, Grond, Stephanie, Böckmann, Rainer A., Steinem, Claudia
• Format: Article
• Language: English
• Subjects: 631/114/2397; 631/154/309/555; 631/326; 631/57/2270/1140; 631/92/56; 9/97; Amino acids; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antimicrobial activity; Antimicrobial agents; Antimicrobial Peptides - chemistry; Antimicrobial Peptides - pharmacology; Bacteria; Black lipid membranes; Cations; Cell Membrane - chemistry; Cell Membrane - drug effects; Cell Membrane - metabolism; Cholesterol; Dissipation; Drug resistance; Gram-positive bacteria; Humanities and Social Sciences; Hydrogen bonding; Lipid membranes; Lipids; Membrane Lipids - chemistry; Membrane Lipids - metabolism; Membrane potential; Membrane Potentials - drug effects; Membranes; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Mode of action; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Nanotechnology; Nanotubes; Nanotubes - chemistry; Peptides; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Protons; Science; Science (multidisciplinary); Spectroscopy, Fourier Transform Infrared; Staphylococcus aureus; Staphylococcus infections; Staphylococcus lugdunensis; Staphylococcus lugdunensis - chemistry; Staphylococcus lugdunensis - drug effects; Staphylococcus lugdunensis - metabolism; Translocation; Water - chemistry
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47803-6

Recently, a novel cyclo-heptapeptide composed of alternating d , l -amino acids and a unique thiazolidine heterocycle, called lugdunin, was discovered, which is produced by the nasal and skin commensal Staphylococcus lugdunensis . Lugdunin displays potent antimicrobial activity against a broad spectrum of Gram-positive bacteria, including challenging-to-treat methicillin-resistant Staphylococcus aureus (MRSA). Lugdunin specifically inhibits target bacteria by dissipating their membrane potential. However, the precise mode of action of this new class of fibupeptides remains largely elusive. Here, we disclose the mechanism by which lugdunin rapidly destabilizes the bacterial membrane potential using an in vitro approach. The peptide strongly partitions into lipid compositions resembling Gram-positive bacterial membranes but less in those harboring the eukaryotic membrane component cholesterol. Upon insertion, lugdunin forms hydrogen-bonded antiparallel β-sheets by the formation of peptide nanotubes, as demonstrated by ATR-FTIR spectroscopy and molecular dynamics simulations. These hydrophilic nanotubes filled with a water wire facilitate not only the translocation of protons but also of monovalent cations as demonstrated by voltage-clamp experiments on black lipid membranes. Collectively, our results provide evidence that the natural fibupeptide lugdunin acts as a peptidic channel that is spontaneously formed by an intricate stacking mechanism, leading to the dissipation of a bacterial cell’s membrane potential. The fibupeptide lugdunin has shown activity against antibiotic-resistant bacteria. Here, authors disclose its mechanism of action in lipid membranes and demonstrate that it assembles into nanotubes facilitating the translocation of monovalent cations.