Functional and structural analysis of a potential therapeutic target in Clostridium difficile
Project Supervisors: Professor Nigel P Minton & Dr Max Paoli
Clostridium difficile-associated diarrhoea (CDAD) is one of the most frequently occurring healthcare associated infections in UK hospitals, and is currently killing 2-3 times more people in the UK than MRSA. Despite its importance, our basic understanding of the molecular basis of virulence remains woefully inadequate. This has been largely a consequence of the absence of gene tools. The genome sequence has now been determined, and the genetic tools necessary for their manipulation developed at the University of Nottingham.
A gene/gene product has been identified which is essential to cell growth. This PhD project seeks to assess the suitability of this protein as a target for therapeutic drugs. The objectives are to characterise the role of the encoded protein in cell physiology at both the genetic and protein level. This will involve the analysis of gene regulation using microarray technology. Biochemical analyses, including determination of substrate specificity and kinetic constants, will be carried out with the cloned and overexpressed enzyme. Purified material will form the basis of an X-ray crystallography study. Structural data will define the geometry of the active site and will thus pave the way for structure-guided design of potential inhibitors as candidates for anticlostridial agents.
The project will involve the application of a combination of biochemical and genetic approaches, including the use of DNA microarrays, X-ray crystallography and computer-aided drug design. The outcomes of these studies should lead to the development of more effective countermeasures against Clostridium difficile.
Students should have a first or 2i honours degree in biological/biomedical sciences. Those with a 2.2, but with a relevant MSc or MPhil will also be considered.
Due to funding restrictions, this studentship, which is available from 1 October 2007, only provides funding for students from the UK/Europe.
Applications with a detailed CV and the names and addresses of two referees, should be sent to Mrs D Mitchell, Centre for Biomolecular Sciences, School of Molecular Medical Sciences, The University of Nottingham, University Park, Nottingham, NG7 2RD. Email: Diane.Mitchell@Nottingham.ac.uk.
Reference : MED117
Closing Date : Open until filled
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