Novel strategy to tackle multidrug-resistant Staphylococcus aureus. (360G-Wellcome-107988_Z_15_Z)

Our preliminary data suggested mannitol-1-phosphate-5-dehydrogenase, a key enzyme in the mannitol pathway in Streptococcus aureus, as a promising therapeutic target, which is not subject to the antibiotic-resistant mechanism of the bacterium. To develop this hypothesis into a major project, we propose a research project aimed at validating our concept also in multidrug-resistant Streptococcus aureus, and characterising mannitol-1-phosphate dehydrogenase biochemically and structurally. To fulfil this aim, we will achieve following specific objectives: 1. Validation of the mannitol-1-phosphate-5-dehydrogenase as a novel target in multidrug-resistant Streptococcus aureus; 2. Kinetic characterisation of mannitol-1-phosphate-5-dehydrogenase; 3. Determination of the X-ray crystal structure of the free enzyme and complex with substrates or inhibitors to provide a framework for the inhibitor development; 4. Preliminary screening of commercial and open access inhibitor libraries as a basis for further inhibitor development. At the end of the project, we will have sufficient data and strong rationale that will place us in positon to stage a main project directed at developing a general strategy that exploits the inhibition of mannitol-1-phosphate-5-dehydrogenase for treating multidrug-resistant pathogens.