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

Dominik Ruppelt, Marius F. W. Trollmann, Taulant Dema, Sebastian N. Wirtz, Hendrik Flegel, Sophia Mönnikes, Stephanie Grond, Rainer A. Böckmann () and Claudia Steinem ()
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Dominik Ruppelt: Georg-August-Universität
Marius F. W. Trollmann: Friedrich-Alexander-Universität Erlangen-Nürnberg
Taulant Dema: Eberhard Karls Universität Tübingen
Sebastian N. Wirtz: Eberhard Karls Universität Tübingen
Hendrik Flegel: Georg-August-Universität
Sophia Mönnikes: Georg-August-Universität
Stephanie Grond: Eberhard Karls Universität Tübingen
Rainer A. Böckmann: Friedrich-Alexander-Universität Erlangen-Nürnberg
Claudia Steinem: Georg-August-Universität

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47803-6

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