Team:Dundee

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Revision as of 23:54, 12 September 2012

Six, Lyse and Obliterate: a synthetic silver bullet against healthcare acquired infection. Hospital acquired infections are a global problem. One example is Clostridium difficile, a bacterial pathogen that infects patients undergoing prolonged antibiotic treatment and results in pseudomembranous colitis, a potentially fatal gut infection. This project aimed to design a synthetic bacterium that would respond to C. difficile infection and kill the pathogen in situ. Escherichia coli was engineered to secrete an endolysin from a bacteriophage that would specifically attack the C. difficile cell wall. The endolysin was fused to the extracellular components of an engineered Type VI Secretion System from Salmonella, which itself comprised 13 different proteins. In addition, a synthetic ‘inflammation biosensor’ was developed, based on a two-component system from Salmonella, with the aim of restricting endolysin secretion to the diseased colon only. Mathematical modelling was used to assist in the development of the laboratory work and to investigate potential therapeutic strategies beyond the scope of the experimental programme.

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-<div><i>Clostridium difficile (C. diff)</i> - associated disease of the gut is a major health problem, and current treatment methods are both ineffective and unpalatable.  Previous research identified a <i>C. diff</i>-specific endolysin from the phage ΦCD27, which could be used to kill <i>C. diff</i> cells. Type VI secretions systems, found in a variety of organisms including <i>Salmonella typhimurium</i>, are characterised by a needle structure, the primary component of which is encoded by the gene Hcp. The tip of the needle is encoded by <i>VgrG</i>. The aim of this project was to create a new type of synthetic <i>Escherichia coli</i> expressing a simplified version of the Type VI Secretion System, with the <i>C. diff</i>-specific endolysin fused to VgrG, and which could be delivered to the gut to combat serious <i>C. diff</i> infections. Mathematical modelling was used to assist in the biological planning and a variety of relevant software applications were made.</div>
+<b>Six, Lyse and Obliterate: a synthetic silver bullet against healthcare acquired infection.</b>
+Hospital acquired infections are a global problem. One example is <I>Clostridium difficile</I>, a bacterial pathogen that infects patients undergoing prolonged antibiotic treatment and results in pseudomembranous colitis, a potentially fatal gut infection. This project aimed to design a synthetic bacterium that would respond to <I>C. difficile</I> infection and kill the pathogen in situ. Escherichia coli was engineered to secrete an endolysin from a bacteriophage that would specifically attack the <I>C. difficile</I> cell wall. The endolysin was fused to the extracellular components of an engineered Type VI Secretion System from Salmonella, which itself comprised 13 different proteins. In addition, a synthetic ‘inflammation biosensor’ was developed, based on a two-component system from Salmonella, with the aim of restricting endolysin secretion to the diseased colon only. Mathematical modelling was used to assist in the development of the laboratory work and to investigate potential therapeutic strategies beyond the scope of the experimental programme.
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