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Open AccessArticle

Plant Polyphenols Inhibit Functional Amyloid and Biofilm Formation in Pseudomonas Strains by Directing Monomers to Off-Pathway Oligomers

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Biotechnology Group, Faculty of Chemical Engineering, Tarbiat Modares University, P.O. Box 14115-143, Tehran, Iran
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Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, 8000 Aarhus C, Denmark
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Department of Biomedicine-Medical Microbiology and Immunology, Aarhus University, 8000 Aarhus C, Denmark
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Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box: 1417863171, Tehran, Iran
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Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen Ø, Denmark
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Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
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Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark
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Authors to whom correspondence should be addressed.
Biomolecules 2019, 9(11), 659; https://doi.org/10.3390/biom9110659
Received: 4 October 2019 / Revised: 19 October 2019 / Accepted: 23 October 2019 / Published: 26 October 2019
(This article belongs to the Section Molecular Structure and Dynamics)
Self-assembly of proteins to β-sheet rich amyloid fibrils is commonly observed in various neurodegenerative diseases. However, amyloid also occurs in the extracellular matrix of bacterial biofilm, which protects bacteria from environmental stress and antibiotics. Many Pseudomonas strains produce functional amyloid where the main component is the highly fibrillation-prone protein FapC. FapC fibrillation may be inhibited by small molecules such as plant polyphenols, which are already known to inhibit formation of pathogenic amyloid, but the mechanism and biological impact of inhibition is unclear. Here, we elucidate how polyphenols modify the self-assembly of functional amyloid, with particular focus on epigallocatechin gallate (EGCG), penta-O-galloyl-β-d-glucose (PGG), baicalein, oleuropein, and procyanidin B2. We find EGCG and PGG to be the best inhibitors. These compounds inhibit amyloid formation by redirecting the aggregation of FapC monomers into oligomeric species, which according to small-angle X-ray scattering (SAXS) measurements organize into core-shell complexes of short axis diameters 25–26 nm consisting of ~7 monomers. Using peptide arrays, we identify EGCG-binding sites in FapC’s linker regions, C and N-terminal parts, and high amyloidogenic sequences located in the R2 and R3 repeats. We correlate our biophysical observations to biological impact by demonstrating that the extent of amyloid inhibition by the different inhibitors correlated with their ability to reduce biofilm, highlighting the potential of anti-amyloid polyphenols as therapeutic agents against biofilm infections. View Full-Text
Keywords: bacterial amyloid; FapC protein; extracellular matrix; aggregation inhibitor; peptide array bacterial amyloid; FapC protein; extracellular matrix; aggregation inhibitor; peptide array
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Najarzadeh, Z.; Mohammad-Beigi, H.; Nedergaard Pedersen, J.; Christiansen, G.; Sønderby, T.V.; Shojaosadati, S.A.; Morshedi, D.; Strømgaard, K.; Meisl, G.; Sutherland, D.; Skov Pedersen, J.; Otzen, D.E. Plant Polyphenols Inhibit Functional Amyloid and Biofilm Formation in Pseudomonas Strains by Directing Monomers to Off-Pathway Oligomers. Biomolecules 2019, 9, 659.

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