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

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 spect...

Full description

Saved in:

Bibliographic Details
Published in:	Nature communications Vol. 15; no. 1; p. 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:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 25-04-2024 Nature Publishing Group Nature Portfolio
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
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-47803-6