Completed Infection & Immunity Cells, Biochemistry & Physiology

Structural and functional characterisation of cell wall proteins of Clostridium difficile.

Funder MRC (part of UKRI)
Recipient organisation Imperial College London
Funding £1.4M
Period Aug 2008 — Dec 2013

In plain English

AI plain-English summary

The surface proteins that coat *Clostridium difficile* are the bacterium's key to unlocking a gut infection, and this project will map their molecular shapes for the first time. *C. difficile* causes severe, sometimes fatal diarrhoea, particularly in hospitalised elderly patients. Infection rates are rising across the UK, driven by antibiotic use that clears the gut of competing bacteria. The first step in every infection is colonisation—the bacteria must stick to the gut wall. No vaccine exists, and antibiotic treatments often fail. The core problem is that researchers know very little about the surface proteins that make colonisation possible, so they cannot design drugs to block them. This project will use biochemical techniques to determine the three-dimensional structures of these surface proteins from three common UK strains. It will also test whether one of these proteins can trigger a protective immune response in animals. If successful, this work will provide the first detailed molecular blueprints of *C. difficile*'s colonisation machinery. Those blueprints could directly inform the design of new vaccines or drugs that prevent the bacteria from ever establishing an infection—stopping disease before it starts. This is fundamental science with a clear translational target: a concrete step toward a vaccine for a stubborn hospital pathogen.

View original technical description
The bacterium Clostridium difficile can cause serious intestinal infections, and elderly patients in hospitals are particularly at risk. Rates of infection are increasing in the UK and elsewhere, and infection is linked to the widespread of use antibiotics. The first step in an infection is when the bacteria colonise the gut, where they then grow and cause disease. At present we cannot prevent colonisation, and so the bacteria are free to multiply and produce toxins that cause diarrhoea and other potentially fatal symptoms. There is no vaccine against C. difficile, and treatment with antibiotics is not always effective. Developing new therapies and treatments against C. difficile is essential, but this is very difficult because we know little about the bacterium. We do know that on the outside of the bacteria there are many surface proteins. These proteins are essential for colonisation, and if we can interfere with their functions we will be able to prevent disease. In this project we will study the surface proteins. We will use several biochemical techniques to unravel their molecular structures, discovering exactly what the proteins look like. We will also explore how the proteins fit together on the surface of the bacterium. Not all strains of C. difficile are identical, and in this project we will investigate three strains that are particularly prevalent in the UK. We will also perform a limited vaccination study in animals.The information we will gain will help enormously in the design of new inhibitors of colonisation or in new vaccines against infection.

View the original record at the funder ↗

Researchers

Katherine Brown (Co-Investigator)Neil Fairweather (Principal Investigator)

Related Research

Grants with similar aims, by meaning.

Structure-function studies on Clostridium difficile large toxins
Role of surface proteins in clostridium difficile infection
Structure and interactions of the Clostridium difficile S-layer with bacteriocins.
Investigating molecular mechanisms of Clostridium difficile colonisation
Genetic, structural and functional analyses of flagellar glycosylation in epidemic Clostridium difficile strains

Original classification

Research Grant

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