Elucidation of the Molecular Mechanism of Staphylococcus aureus response to cell wall damage

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The proposed research program aims understanding the Staphylococcus aureus response to cell wall damage. Bacterial cell wall is the first line of defense in bacteria and as such its integrity is under constant stress. Cell wall in Gram-positive bacteria consists of a glycopeptide polymer, referred to as peptidoglycan, and a polyanionic polymer covalently attached to peptidoglycan, referred to as wall teichoic acid. Integrity of both polymers is indispensable to bacterial cell growth and division, and in the case of pathogenic bacteria they are indispensable to colonization and host infection. Genome-based studies on profiling the activity of cell wall inhibitors have revealed that bacteria in general and S. aureus is particular have complex signaling mechanisms in place to sense and respond to cell wall damage. A number of signal transduction and metabolic pathways appear to be involved with the response to cell wall damage, independent of where in the pathway the damage occurs. The details of how the signal-transduction pathways function and work together to respond to cell wall damage are lacking. The proposed research program focuses on the molecular mechanisms of signal-transduction by two-component systems VraSR and GraSR and the eukaryotic- like serine/threonine kinase/phosphatase Stk1/Stp of S. aureus. VraSR is considered the sentinel of cell wall integrity. My group was the first to provide the kinetics of signal-transduction by VraSR and revealed the regulatory mechanism of VraR (Belcheva et al. J. Biol. Chem, 2008; Belcheva et al.  Biochemistry 2009). Recent reports show that S. aureus may involve another protein in tuning signaling by VraSR, VraT. GraSR is involved in modulation of wall teichoic acid, and our current research indicates that GraS utilizes a different mechanism than VraSR for signaling (Muzamal et al. F1000 Prime, 2014). Stk1/Stp is involved in regulation of cell wall synthesis and was shown by our group to interact with GraSR (Fridman et al. Biochemistry, 2013). Moreover, we recently discovered that Stk1/Stp phosphorylates a protein involved with cell wall synthesis. The objectives of the proposal are two-fold: understand signaling mechanisms of the above systems and their interplay in S. aureus response to cell wall damage. My laboratory has expertise in protein chemistry, molecular biology and microbiology to achieve the above objectives. The proposed research program constitutes a basic research on stress response mechanisms, gene functions and regulation in S. aureus. The knowledge anticipated to be gained in this program will be of great interest to research communities involved in studies of microbial stress responses, cell wall biosynthesis and gene regulation.