): The widespread emergence of antibiotic resistant bacteria poses a grave threat to our ability to manage and control infectious disease. While tremendous progress has been made in understanding the role of transmissible plasmids and high-level resistance genes in antibiotic resistance, the role and regulation of chromosomally-encoded determinants is less well understood. This project focuses on the genetically well characterized model organism Bacillus subtilis, to investigate the functional genomics of antibiotic resistance and responses. The close evolutionary between B. subtilis and important human pathogens (especially Staphylococcus aureus, Mycobacterium tuberculosis, Enterococcus, and Streptococcus), allows knowledge gained in our system to be directly used in understanding the other. The goal of this project is to understand the role of alternative sigma factors in coordinating the genetic responses triggered by exposure of B. subtilis to antibiotics that target the cell envelope. Recently, the SigX and SigW regulators have been found to activate transcription of a large number of genes affecting the structure and function of cell surface polymers, antibiotic resistance mechanisms, and the production of antimicrobial peptides. Expression of these sigma factors is strongly induced by several clinically important antibiotics, including vancomycin and cephalospirins. To better define these genetic responses, and their roles in protecting the cell against antibiotics, two aims will be pursued. First, promoters controlled by each sigma factor will be identified and the rules that govern promoter selectivity will be explored. The identification of target promoters will reveal the complete set of genes (the regulon) activated by each sigma. The PI will define the overlap the overlap between the various regulons controlled by SigX, SigW and other sigma factors.
This aim will include both proteomics and genomics based approaches. Second, the physiological roles of selected taarget genes will also be investigated. For this aim the PI will focus on those operons implicated on defense against antibiotics, modification of the cell envelope, or the production of antimicrobial compounds. In addition, the signaling pathways that control the expression of these regulons will be investigated. Although many different antibiotics can induce each regulon, it is likely that these antibiotics lead to the accumulation of common signaling molecules that are perceived by the anti-sigma factor which then releases the sigma factor. Genetic approaches have been devised to identify components of these signaling pathways. Together, these two aims will provide a unified picture of these two large regulons and their roles in B. subtilis physiology.
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