Staphylococcus aureus infections are a serious problem of public health because of the resistance of this bacteria to most of the in-use antibiotics. Although this microorganism is part of the microbiota, it eventually could cause infections, including cutaneous infections or even cause the death of hospitalized patients due to nosocomial infections. Because of these problems, the research in the development of new therapies that could be used to combat staphylococci infections become a priority in the last years. In this context, the biosynthesis of fatty acid in bacteria is considered an attractive target since it differs considerably from the fatty acid in eukaryotes and it is essential for the survival of prokaryotes. Among the enzymes involved in the biosynthesis of fatty acids, FabH or ²-ketoacyl-ACP synthase III is a promising target because of its key role in this biosynthetic pathway and by several studies that have already been performed aiming the identification of molecules that bind to FabH (SaFabH), in spite of there is no drugs launched in the market targeting this enzyme. Thus, in this project, we are proposing to start the studies aiming the identification of molecules that bind to S. aureus FabH (SaFabH) and that could be considered as hits in the synthesis of new inhibitors with pharmaceutical potential through of the fragment-based drug discovery approach (FBDD). For that, the gene fabH, which was already cloned into the expression vector pET28b, will be transformed in BL21(DE3) competent cells to produce the interest enzyme. FabH will be purified using affinity and size exclusion molecular columns and submitted through a fragment-based drug discovery screening through DSF technique against a library of fragments. The identified molecules will be used in co-crystallization and soaking experiments for future structure determination of the enzyme:fragment complexes, revealing the interaction mode of the fragments. Once we have achieved the objectives of this project, we expect to obtain interesting start point for the synthesis of new inhibitors of SaFABH and that could effectively inhibitors of the enzyme and have biological activity against strains of S. aureus.
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