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EPSRC Reference: EP/C541561/1
Title: Platform: Model Peptides to Novel Antibiotics: Synthesis Form and Activity
Principal Investigator: Barran, Professor PE
Other Investigators:
Govan, Professor J MacMillan, Dr D Uhrin, Professor D
Campopiano, Professor D Wales, Professor D Dorin, Professor jR
Researcher Co-Investigators:
Project Partners:
Department: Sch of Chemistry
Organisation: University of Edinburgh
Scheme: Platform Grants (Pre-FEC)
Starts: 03 October 2005 Ends: 02 October 2010 Value (£): 427,005
EPSRC Research Topic Classifications:
Biological & Medicinal Chem. Chemical Biology
Chemical Structure Medical science & disease
EPSRC Industrial Sector Classifications:
Pharmaceuticals and Biotechnology
Related Grants:
Panel History:  
Summary on Grant Application Form
This proposal brings together a diverse group of scientists with the broad aim of synthesising and characterising new antibiotics. Recently, there has been a worrying rise in bacterial resistance to synthetic antibiotics as well as the emergence of human virulence in already resistant soil bacteria - the so called 'superbugs'. This was not expected 80 years ago when Sir Alexander Fleming discovered penicillin, and it has catalysed a search for novel molecules to fight lifethreatening bacterial infections for which antibiotic options are seriously limited.Humans and other mammals have a rapid, in-built way of dealing with incoming bacteria which is known as the innate immune response. Part of this antimicrobial defence is performed by small proteins know as defensins. Human beings produce about 40 of these, and they are found mainly on parts of the body exposed to the environment. These include the skin, tears, in snot and other bodily secretions. It is thought that defensins work by punching holes in bacterial membranes causing them to burst. However, the precise mechanism of how they work it not known. We have analysed changes in the building blocks (amino acids) that make up the defensin molecules. We know that some amino acids do not change over time, instead they form internal bonds that keep the defensin bundled up in a ball. However, other amino acids in the defensin change rapidly, and we believe this behaviour enables humans to adapt to the changes in bacteria which evolve faster than we do. We want to find out how defensins work. What is the purpose of the rapidly changing and of the conserved amino acids? We need to know the chemical structures of defensins and will evaluate this using molecular modelling, mass spectrometry and NMR. We need to know what effect changing the amino acids has on the antimicrobial activities of these molecules and so we will test them against panels of important pathogens, including some of the most resistant ones.Part of this research will address the interactions between multiple defensin molecules. There is some evidence that they form aggregates, before they interact with membranes, in fact we have studied a dimer (two-molecule) defensin which is much more active than a (one-molecule) monomer. We will try to understand which parts of a defensin allow it to stick together and which parts stick to and kill the bacteria and what bacterial targets are involved. We will examine this phenomena using model cellular environments, both in a 'wet' chemical biology method and also with mass spectrometry and NMR.We want to know which parts of defensin molecules change as bacteria adapt, and which don't make a difference and why? Answering these questions will help us to understand the structure activity relationship of defensins, and help us design new antibiotics which could be used against infections for which therapeutic options are becoming seriously limited.
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