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University of Lincoln RIF Studentships 2014 PROJECT DETAILS Project Title Rational inhibitor design from structural studies of peptidoglycan modifying enzymes Project Reference RIF2014S-52 Project Summary This study aims to investigate the mechanisms of peptidoglycan modulating enzymes and their involvement in bacterial cell wall growth, division and immune evasion. Peptidoglycan is a uniquely bacterial polymer and its biosynthesis is crucial for its growth and proliferation. We seek to highlight their inhibition as targets for new antimicrobial compound development and use our crystallographic data to propose rationally designed transition state analogue inhibitors. The study will utilise a wide variety of molecular biology / biochemical techniques such as the generation of prokaryotic knockout mutants, the cloning and hyperexpression of autolysin genes, protein purification and X-ray crystallography for the determination of protein structures. Society is currently facing a worldwide pandemic of multidrug resistance bacteria, arising from the long-term use of antibiotics. In a clinical setting these strains proliferate under antibacterial treatment, resulting in sepsis and often life-threatening levels of infection. As part of the measures required to counteract this, new antimicrobial compounds are needed. Due to their location and lack of eukaryotic counterpart the bacterial cell wall synthetic machinery present as ideal inhibitory targets for the generation of new antimicrobial compounds. Peptidoglycan is the predominant structural scaffold found in bacterial cell walls. Upon growth, and at cell division, this scaffold is re-worked or “modulated” by a suite of enzymes including autolysins and acetyltransferases. This project will evaluate two classes of peptidoglycan modulating enzymes, the autolysins (GH25) and O-acetyltransferases, as potential inhibitory targets. A combinatorial knockout study will be associated with structural / mechanistic work to enable rational inhibitor design. It will examine the hypothesis that inhibition of peptidoglycan modulating enzymes will have a significant effect on bacterial cell growth and colonization of a host. The aim is to characterise peptidoglycan modifying enzymes and obtain structures complexed with peptidoglycan fragments. Supervisory Team 1. Dr James Flint, Lecturer in Biotechnology, Lincoln School of Life Sciences. http://staff.lincoln.ac.uk/jflint 2. Dr. Edward J. Taylor, Research Fellow, Lincoln School of Life Sciences. http://staff.lincoln.ac.uk/etaylor 3. Dr. Pallavi Sharma, Lecturer, Lincoln School of Life Sciences. http://staff.lincoln.ac.uk/psharma Informal Enquiries For informal enquiries or further information on the study, please contact James Flint by email: [email protected] Eligibility All Candidates must satisfy the University’s minimum doctoral entry criteria for All Candidates must satisfy the University’s minimum doctoral entry criteria for studentships of an honours degree at Upper Second Class (2:1) or an appropriate Masters degree or equivalent. A minimum IELTS (Academic) score of 7 (or equivalent) is essential for candidates for whom English is not their first language. Funded Studentships are open to both UK/EU students unless otherwise specified. How to Apply Please send a covering letter outlining your interest and proposed approach (up to 1 page A4) with an accompanying CV to [email protected] by close of day on 18th April 2014. Candidates will be notified w/c 5th May of the outcome of the process and if invited to interview, these are anticipated to take place w/c 26h May.
