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.