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

Autor: Ruppelt D; Institute of Organic and Biomolecular Chemistry, Georg-August-Universität, Tammannstraße 2, 37077, Göttingen, Germany., Trollmann MFW; Computational Biology, Department Biologie & Erlangen National High Perfomance Computing Center (NHR@FAU), Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstraße 5, 91058, Erlangen, Germany., Dema T; Institute of Organic Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076, Tübingen, Germany., Wirtz SN; Institute of Organic Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076, Tübingen, Germany., Flegel H; Institute of Organic and Biomolecular Chemistry, Georg-August-Universität, Tammannstraße 2, 37077, Göttingen, Germany., Mönnikes S; Institute of Organic and Biomolecular Chemistry, Georg-August-Universität, Tammannstraße 2, 37077, Göttingen, Germany., Grond S; Institute of Organic Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076, Tübingen, Germany., Böckmann RA; Computational Biology, Department Biologie & Erlangen National High Perfomance Computing Center (NHR@FAU), Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstraße 5, 91058, Erlangen, Germany. rainer.boeckmann@fau.de., Steinem C; Institute of Organic and Biomolecular Chemistry, Georg-August-Universität, Tammannstraße 2, 37077, Göttingen, Germany. csteine@gwdg.de.; Max Planck Institute for Dynamics and Self-Organization, Am Faßberg 17, 37077, Göttingen, Germany. csteine@gwdg.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Apr 25; Vol. 15 (1), pp. 3521. Date of Electronic Publication: 2024 Apr 25.
DOI: 10.1038/s41467-024-47803-6
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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