Structure, Function and Regulation of Antimicrobial and Virulent Amyloids at High-resolution
This project aims to elucidate the structure-function relationships of amyloid fibrils in microbial virulence and antimicrobial activity to inform the design of targeted therapies for infectious diseases.
Projectdetails
Introduction
Self-assembly of proteins and peptides into amyloid fibrils produced across kingdoms of life is associated with antimicrobial activity, microbial pathogenicity, and a wide range of diseases. The correlation of fibrillation and morphology to function is poorly understood, and high-resolution structural information and mechanistic models are lacking.
Background
Our lab pioneered the atomic-level analysis of bacterial amyloids and eukaryotic functional fibrils involved in cytotoxicity, biofilm structuring, and antibacterial activity. We revealed novel morphologies extending beyond canonical amyloid cross-β structures of tightly mated β-sheets, to include, for example, cross-α fibrils composed of amphipathic α-helices.
In addition, we exposed a unique lipid-induced cross-α/β secondary structure switch in fibrils of the same sequence.
Research Focus
Here we investigate amyloid fibrils which serve as key virulence determinants in S. aureus and Pseudomonas, acting as cytotoxins and in biofilm scaffolding, and as antimicrobials produced across different species.
Methodology
We will leverage the knowledge and expertise, and newly emerging methods in electron, light, and force microscopy, to understand how:
- Fibrillation propensity
- Fibril morphology
- Structural switches
are connected to function, membrane interactions, and toxicity mechanisms at high resolution.
Expected Outcomes
The findings are expected to identify structural features that underlie the formation, regulation, and activity of these fibrils, providing advantages in specific environments. Understanding these structure-function relationships will help to clarify the link between amyloid formation and antimicrobial activity.
Applications
We will use the insights gained from these studies for the rational design of antimicrobial peptides and small molecules targeting virulent determinants towards potential applications in the management of infectious diseases.
Our findings on functional amyloids can overall advance life, material, medical, and environmental sciences.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 2.000.000 |
Totale projectbegroting | € 2.000.000 |
Tijdlijn
Startdatum | 1-10-2023 |
Einddatum | 30-9-2028 |
Subsidiejaar | 2023 |
Partners & Locaties
Projectpartners
- DEUTSCHES ELEKTRONEN-SYNCHROTRON DESYpenvoerder
- EUROPEAN MOLECULAR BIOLOGY LABORATORY
Land(en)
Vergelijkbare projecten binnen European Research Council
Project | Regeling | Bedrag | Jaar | Actie |
---|---|---|---|---|
Physical and molecular underpinnings of the multifunctionality of bacterial peptide assembliesThis project aims to uncover the self-assembly mechanisms of phenol soluble modulins in Staphylococcus aureus to understand their multifunctionality and develop novel therapeutics against infections. | ERC Starting... | € 1.500.000 | 2025 | Details |
Global Amyloid Mapping: Solving Amyloid Nucleation by Deep MutagenesisThis project aims to map mutations affecting amyloid nucleation, model transition states, and identify stress-responsive sequences to enhance understanding and treatment of amyloid-related diseases. | ERC Consolid... | € 1.999.008 | 2024 | Details |
BiFoldome: Homo- and Hetero-typic Interactions in Assembled FoldomesBiFOLDOME aims to understand co-assembly in amyloids through innovative NMR techniques, enhancing insights into self-assembly and potential applications in disease-related protein manipulation. | ERC Starting... | € 1.496.823 | 2022 | Details |
Supramolecular Self-Replicating AntimicrobialsThis project develops self-replicating supramolecular antimicrobial agents that target bacterial membranes, enhancing therapeutic efficacy through cooperative self-assembly and autocatalysis. | ERC Starting... | € 1.499.496 | 2025 | Details |
Structure and Regulation of Bacterial Biofilm-Promoting Exopolysaccharide Secretion SystemsThe project aims to decode the assembly and function of exopolysaccharide secretion systems in bacteria to develop novel anti-infectives and enhance beneficial EPS production. | ERC Consolid... | € 1.950.000 | 2024 | Details |
Physical and molecular underpinnings of the multifunctionality of bacterial peptide assemblies
This project aims to uncover the self-assembly mechanisms of phenol soluble modulins in Staphylococcus aureus to understand their multifunctionality and develop novel therapeutics against infections.
Global Amyloid Mapping: Solving Amyloid Nucleation by Deep Mutagenesis
This project aims to map mutations affecting amyloid nucleation, model transition states, and identify stress-responsive sequences to enhance understanding and treatment of amyloid-related diseases.
BiFoldome: Homo- and Hetero-typic Interactions in Assembled Foldomes
BiFOLDOME aims to understand co-assembly in amyloids through innovative NMR techniques, enhancing insights into self-assembly and potential applications in disease-related protein manipulation.
Supramolecular Self-Replicating Antimicrobials
This project develops self-replicating supramolecular antimicrobial agents that target bacterial membranes, enhancing therapeutic efficacy through cooperative self-assembly and autocatalysis.
Structure and Regulation of Bacterial Biofilm-Promoting Exopolysaccharide Secretion Systems
The project aims to decode the assembly and function of exopolysaccharide secretion systems in bacteria to develop novel anti-infectives and enhance beneficial EPS production.