Most bacteria form biofilms to survive under stress-inducing conditions by achieving a communal living. The biofilm associated pathogenic microbes are resistant to antimicrobial agents and host immune system, as a result they are more infectious and difficult to treat. Amyloid fibrils are the most crucial components supplying the structural integrity of biofilms, so the antimicrobial resistance. However, very little structural information is known on biofilms and their amyloid proteins. Understanding the structural features forming biofilm integrity, by focusing particularly on the amyloid proteins, is an important step towards development of successful therapeutics for infectious bacteria protected in robust biofilms.
The primary goal of my project is to determine the first atomic-resolution structures of biofilm forming functional amyloids from different bacteria, by using advanced solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy. Starting from these structural insights, I aim to understand fibril formation in function and disease, the role of amyloids in biofilms, ways of controlling or preventing biofilm formation in the associated chronic diseases, and finally, the structural switch of proteins between soluble, oligomeric and fibrillar states.
The system I am working on is a unique example for having a globular soluble monomeric fold, among all known functional amyloids from bacterial biofilms. This is an exciting opportunity to get the initial states of functional amyloid formation in biofilms, by studying the monomer and following structural changes along its incorporation into biofilm matrix: from soluble monomeric fold, via intermediate states into oligomeric or fibrillar folds. As a novel structural biology approach, I aim to develop and establish the way towards in-vivo structural biology. This will be achieved by utilising high-sensitivity ssNMR methods: proton-detection & hyperpolarization via DNP.
The project is highly interdisciplinary and combines physical chemistry techniques with biochemistry and biology. The results obtained from my research will be of great importance for understanding and treating functional amyloid related diseases caused by bacterial biofilms. As a result, clever design and optimization of anti-biofilm drugs targeting fibrils can be achieved. Already received funding from Denmark and EU, via DFF MOBILEX and AIAS COFUND, supports solid progress of the project.
Structural Biology of Bacterial Functional Amyloids: In Biofilms, Fibril Formation and Infection
Area of research:
01 Feb 2015 – 31 Jan 2018