Plant polyphenols inhibit functional amyloid and biofilm formation in Pseudomonas strains by directing monomers to off-pathway oligomers

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  • Zahra Najarzadeh, Tarbiat Modares University
  • ,
  • Hossein Mohammad-Beigi
  • ,
  • Jannik Nedergaard Pedersen
  • Gunna Christiansen
  • ,
  • Thorbjørn Vincent Sønderby
  • Seyed Abbas Shojaosadati, Tarbiat Modares University
  • ,
  • Dina Morshedi, National Institute of Genetic Engineering and Biotechnology
  • ,
  • Kristian Strømgaard, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, University of Copenhagen
  • ,
  • Georg Meisl, University of Cambridge
  • ,
  • Duncan Sutherland
  • Jan Skov Pedersen
  • Daniel Otzen

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.

Original languageEnglish
Article number659
Publication statusPublished - 1 Nov 2019

    Research areas

  • Aggregation inhibitor, Bacterial amyloid, Extracellular matrix, FapC protein, Peptide array

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