ANTI-MICROBIALS – MEDICINAL CHEMISTRY Timothy Curd - Sunderland University - Supervised by Mark Ashton and Dr Yu Gong. Special acknowledgement to the Nuffield foundation for funding my project. Antibiotics have been used in medicine for decades, but a growing problem is antibiotic resistance. This project aims to explore how taking advantage of Quorum sensing between Bacterium can aid in the treatment of Bacterial infections. Quorum sensing is a mechanism used by Bacteria to communicate between each other by producing and secreting signalling molecules. A single Bacterium would have little or no impact on an individual, however, beyond a reasonable population size – symptoms can begin to develop. Quorum sensing allows Bacteria to gauge an idea of how large or small the population is. Once the bacterial population is large enough, further communication takes place – and the entire population of Bacteria may begin to behave in a certain manner – such as to secrete toxins. Quorum sensing effectively allows the population of Bacteria to behave like a multi- cellular organism. Biologist Bonnie Bassler looked into a bioluminescent Bacterium, Vibrio fischeri. When an individual Bacterium was suspended, no light was emitted. However, when a population of the Bacteria was created, light was emitted. This suggested that the Bacteria communicated between each other signalling when to start emitting light. It was also clear that only beyond a certain population size light was emitted, and therefore the deduction that the Bacterium was also able to gauge an idea of population size through the chemical signalling could be made. Suitable population size reached – light emitted Small population size – no light emitted Single Bacterium – no light emitted Analysis techniques we used included Infra-red, mass and NMR spectroscopy. We generally used Infra-red during early testing stages to look for functional group differences, NMR was used when we had produced the final product to effectively check the product. Practical work examples After completing initial research, we began practical work – synthesising molecules that would be effective in blocking the signalling between Bacteria by binding to the protein receptor sites. Starting material – 2-Amino-tertiary-butylphenol Starting material – 2-Amino-4-phenylphenol Starting material - 4-Amino-3-hydroxybenzoic acid (Two stage reaction) Part two Same procedure as above, reacting product from Part A with CDI to form target material: Molecular modelling allowed us to see whether our products would bind effectively to the target protein’s Receptor site. The target protein, the binding site highlighted in red The binding site residues Examples of one of my products interacting with the protein receptor site Conclusion Whilst we were able to get a rough idea of whether our materials would be successful using Molecular modelling, testing with Bacterial lines is required. A full conclusion of whether our compounds have been successful will only be available after we receive results from the Microbiology department – testing our Products on Bacterial lines to see what impact, if any the compounds are having on the Population of Bacteria. Despite this project being complete for us, the work of scientists all over the world continues in this field as we strive to find the ‘next generation’ of Antibiotics.