Lipoate Metabolism in Staphylococcus Aureus Pathogenesis

Lipoate is an essential cofactor of several proteins involved in cellular energy homeostasis and catabolism. Lipoate metabolism has been linked to pathogenesis in some microbial species, but its role in Staphylococcus aureus infections had not been explored. In this thesis, we tested the hypothesis that lipoate acquisition mechanisms promote S. aureus infectivity. We used a bacterial genetics approach to elucidate the biological function of the S. aureus genes involved in lipoate metabolism. Our findings allowed us to propose a model for lipoic acid de novo biosynthesis and salvage pathways in S. aureus. Moreover, we detail hitherto undescribed genetic arrangements of lipoate de novo biosynthesis and salvage genes in the S. aureus genome, which suggest a potential role for lipoate acquisition mechanisms in metabolic regulation and oxidative stress defense. Also, we have identified critical requirements for gene products involved in lipoate metabolism in murine sepsis. Our data indicate that S. aureus is capable of using bacterial and host-derived lipoate during infection in a tissue-specific manner, thereby promoting survival in diverse nutrient-restricted environments. Overall, our findings suggest that the S. aureus lipoate de novo biosynthesis and salvage pathways offer potential for the development of novel therapeutics that target key metabolic programs in S. aureu