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In situ captured antibacterial action of membrane-incising peptide lamellae.

ABSTRACT: Developing unique mechanisms of action are essential to combat the growing issue of antimicrobial resistance. Supramolecular assemblies combining the improved biostability of non-natural compounds with the complex membrane-attacking mechanisms of natural peptides are promising alternatives to conventional antibiotics. However, for such compounds the direct visual insight on antibacterial action is still lacking. Here we employ a design strategy focusing on an inducible assembly mechanism and utilized electron microscopy (EM) to follow the formation of supramolecular structures of lysine-rich heterochiral β³-peptides, termed lamellin-2K and lamellin-3K, triggered by bacterial cell surface lipopolysaccharides. Combined molecular dynamics simulations, EM and bacterial assays confirmed that the phosphate-induced conformational change on these lamellins led to the formation of striped lamellae capable of incising the cell envelope of Gram-negative bacteria thereby exerting antibacterial activity. Our findings also provide a mechanistic link for membrane-targeting agents depicting the antibiotic mechanism derived from the in-situ formation of active supramolecules.

SUBMITTER: El Battioui K

PROVIDER: S-EPMC11039730 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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In situ captured antibacterial action of membrane-incising peptide lamellae.

El Battioui Kamal K Chakraborty Sohini S Wacha András A Molnár Dániel D Quemé-Peña Mayra M Szigyártó Imola Cs IC Szabó Csenge Lilla CL Bodor Andrea A Horváti Kata K Gyulai Gergő G Bősze Szilvia S Mihály Judith J Jezsó Bálint B Románszki Loránd L Tóth Judit J Varga Zoltán Z Mándity István I Juhász Tünde T Beke-Somfai Tamás T

Nature communications 20240423 1

Developing unique mechanisms of action are essential to combat the growing issue of antimicrobial resistance. Supramolecular assemblies combining the improved biostability of non-natural compounds with the complex membrane-attacking mechanisms of natural peptides are promising alternatives to conventional antibiotics. However, for such compounds the direct visual insight on antibacterial action is still lacking. Here we employ a design strategy focusing on an inducible assembly mechanism and uti ...[more]

PMID: 38654023

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Project description:Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics in the fight against multidrug-resistant pathogens. Here, we characterize the antibacterial properties and molecular mode of action of the C-terminal fragment of the Medicago truncatula nodule-specific cysteine-rich peptide NCR169 (NCR169C17-38). This peptide exhibits strong bactericidal activity against a broad panel of Gram-positive and Gram-negative pathogens, including members of the ESKAPE group (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli). NCR169C17-38 acted rapidly by permeabilizing bacterial membranes and causing severe morphological damage, outperforming polymyxin B in the rate of membrane disruption. The peptide bound selectively to anionic bacterial lipids such as cardiolipin and displayed remarkable thermal and storage stability. Moreover, NCR169C17-38 effectively inhibited biofilm formation and eradicated pre-formed biofilms of Acinetobacter baumannii even at sub-MBC concentration (3.2 M), a feature not observed for polymyxin B. Transcriptomic analysis of Escherichia coli exposed to sublethal peptide doses revealed a global shutdown of bacterial metabolic and genetic functions, with 450 of 503 differentially expressed genes being downregulated. Strong repression of genes involved in translation, energy production, and cell envelope biosynthesis was accompanied by upregulation of stress- and rescue-related genes linked to membrane repair, ion transport, and oxidative stress responses. Together, these results demonstrate that NCR169C17-38 exerts multifaceted antimicrobial effects - disrupting membranes, binding nucleic acids, and inducing transcriptional collapse - while maintaining its stability and biocompatibility. Together with its previously established antifungal activity and lack of mammalian cytotoxicity, NCR169C17-38 represents a compelling candidate for development as a next-generation antimicrobial agent.

Dataset Information

In situ captured antibacterial action of membrane-incising peptide lamellae.

Publications

In situ captured antibacterial action of membrane-incising peptide lamellae.

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