Structural biochemistry of enzymes involved in biosynthesis of c-di-AMP in Staphylococcus aureus

Abstract

Staphylococcus aureus is an important human pathogen that colonizes mainly the nostrils and skin, leading to a series of invasive infections. Recently, the number of infections caused by strains resistant to several super antibiotics indicates the need to search for new treatments. Accordingly, new targets for drug development have been explored and bacterial cell wall, which structures are essential for infection, appears as a grat opportunity for research. It has been shown that one of these structures, the lipoteichoic acid (LTA), is essential for the growth of super-resistant strains of S. aureus, but even mutants unable to synthesize LTA recovered almost normal growth after an additional mutation in the phosphodiesterase Sa_GdpP. Together with the di-adenylate cyclase Sa_DacA, Sa_GdpP is responsible for the maintenance of intracellular levels of the new bacterial signaling molecule c-di-AMP. In S. aureus, increased levels of this molecule enhances the ability of bacteria to deal with cell wall stress. Seeking a better of c-di-AMP turnover in S. aureus, this project aims at solving the three-dimensional structures of Sa_GdpP Sa_DacA through X-ray crystallography. Coupled to this technique, we will employ biophysical and biochemical characterization in order to propose mechanisms of activity for these two enzymes. The results generated in this project may provide a basis for the development of new therapies against the infection of super-resistant strains of S. aureus.