Grant: Discovery Grants Program - Individual

Research in my laboratory is focused on understanding the Staphylococcus aureus response to antibacterial agents that target cell wall biosynthesis, namely cell wall inhibitors, and its role to antibiotic resistance. We are using information from genome-based research to elucidate the signaling pathways involved with cell wall damage response. We have undertaken the study of a two-component signal transduction system, VraSR, which was shown in vivo to be essential to the S. aureus response against cell wall damage (stress) and to be involved in resistance to cell wall inhibitors. The VraSR system is composed of a membrane bound sensor protein, VraS, a histidine kinase, and a cytoplasmic response regulatory protein VraR, a transcription factor. Our initial studies indicate that VraSR is capable of rapidly transducing and reliably eliciting a response to cell wall stress via a non-branched mechanism. Further, we are in the process of understanding the global gene-regulatory mechanism of VraR and unraveling the functions of genes that are involved with the bacterial response to cell wall stress. The above studies have paved the road for an in depth research of the mechanism of S. aureus response to cell wall stress. The the proposed research program aims 1) Elucidation of the molecular mechanism that underlines the S. aureus response to cell wall inhibitors; and 2) Identification of the signal(s) elicited upon cell wall damage. We are using molecular biology and biochemical approaches to achieve our objectives. The electrophoretic mobility assays, DNaseI footprinting, in vitro transcription and reporter vectors are some of the tools that will be used in this study. Our laboratory has established expertise in all the above areas and collaborations are established to provide an in depth investigation of the systems of interest. The proposed research program constitutes a basic research on gene function and regulation and stress response mechanisms 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 response, cell wall biosynthesis and gene regulation. The novelty of the study is two-fold: First it aims the understanding of the role that cell wall plays in coordinating bacterial response to cell wall stress and the signal transduction mechanisms involved with maintaining the integrity of cell wall during assault; and Second, it aims at understanding the mode-of-action of the antibiotics. Both these aims will change how we look at the antibiotics and how infectious diseases could be treated successfully without giving rise to antibiotic resistance.