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PhD Summary

PhD Supervisors:

Dr. David Roper, Structural Biology, The University of Warwick

Professor Tim Bugg, Chemical Biology, The University of Warwick

PhD Title: Exploration and Analysis of Penicillin-Binding Proteins as Synthetic Tools and Targets

Peptidoglycan is a structurally vital component of the bacterial cell wall and its biosynthesis is heavily targeted by antibacterial therapeutics. Resistance mechanisms have evolved naturally in bacteria to evade destruction by antibiotics, which has recently assisted the emergence of nosocomial infections such as MRSA and VRE. This project aims to further investigate the structure and function of Penicillin-Binding Proteins (PBPs) in Gram-negative bacteria, with a focus to develop an assay for the full characterisation of the dual-activity of bifunctional PBPs. The mesh-like structure of peptidoglycan within the cell wall consists of aligned glycan strands, which are cross-linked to each other via a peptide bridge. PBPs have a role in the building and cross-linking of these glycan strands. Synthesis of the glycan strand is to be tracked in real-time by Linear Dichroism. PBP activity is to be enzymatically characterised using biochemical and biophysical techniques, radio- and fluorescence-labelling and lipid-linked reagent chemistry. Advances in chemical probe and substrate design at Warwick will aid this project, with chemical synthesis being used to harvest compounds required for assays. Mutants will be made by traditional molecular biology techniques to further elucidate the precise role of individual PBP domains. A detailed understanding of peptidoglycan synthesis is of immediate interest to the pharmaceutical industry, since it will enable the design and application of novel assays to detect inhibitors of peptidoglycan polymerisation.