"Clostridium difficile infection (CDI) represents the most problematic hospital acquired infection in Europe. It is also increasingly recognized as a community-associated disease. Current treatments for C. difficile disease are inadequate and other strategies must be found to treat or prevent disease. C. difficile is an anaerobic Gram-positive, spore-forming enteric pathogen. After disruption of the intestinal barrier by antibiotics, spores of C. difficile germinate and bacteria multiply in the intestine. Toxins are released and cause symptoms of disease which include diarrhea, or in the worst case, pseudomembranous colitis.The crucial early step of C. difficile infection is colonization of the intestine. C. difficile, like most bacterial pathogens, displays proteins on its surface that may act as adhesins and facilitate interaction with the host in order to allow colonization.
Gram-positive bacteria predominantly use their thick cell wall as a platform for display of surface proteins. Cell wall surface proteins can be covalently linked to the peptidoglycan by a sortase enzyme, a membrane-associated transpeptidase. Sortase enzymes and their substrates are promising therapeutic targets for the development of novel antibiotics. To date no sortase enzyme or substrates have been described in C. difficile, although we have identified several sortase and sortase substrate genes within the genome.
The project described here will investigate the role of the C. difficile sortase enzyme and sortase substrates. A variety of state-of-the art techniques will be used to explore these proteins, including advanced molecular genetics, in vivo animal models of infection and structural biology. The characterization of sortase enzymes and sortase substrates will allow firstly a better understanding of the colonization process of C. difficile and secondly will allow the identification of new virulence factors, which constitute potential vaccine components."
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