October 23, 2015
Early stages of structural development of antibiotics through probing of dihydroneopterin aldolase binding sites
Antibiotics is an ever growing topic in research. This is due to its need in our society and the rising rate of bacterial resistance to them. Our lab employed X-ray crystallography and a number strategies to design new antibiotics that bacteria are less susceptible to become resistant to due to random mutation. First we targeted pathway proteins, where all other enzymes along the pathway have very similar ligands. Our lab chose to work with the protein dihydroneopterin aldolase, DHNA, in the folate pathway, whose lack of a parallel in humans also decreases the chances of adverse side effects. Second our lab is investigating DHNA across bacteria species, in Yersinia pestis, Escherichia coli, and Staphylococcus aureus. Third through fragment binding, our lab tries to analysis the binding site by crystalizing DHNA with small varying fragments. In the first of many probes we were able to successfully co-crystalize Y. pestis with pterin, revealing a conformational change in the binding site which could prove invaluable to further investigation. Through these probes we hope to get an idea of what fragments will bind and under what conditions. Ultimately after more fragment runs we will be able to put the successfully binding fragments together and test it’s potential as an inhibitor of DHNA.
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