Transcription Factors, Sigma Factors, and Regulatory RNAs Coordinate and Integrate the Staphylococcus aureus Stress Response

Abstract

Staphylococcus aureus infections impose a serious economic burden on healthcare facilities and patients because of the emergence of strains resistant to last-line antibiotics. Understanding the physiological processes governing fitness and virulence of S. aureus in response to environmental cues is critical for developing efficient diagnostics and treatments. CodY is an important global regulator that links the physiological state of the cell to the production of virulence factors in response to the availability of GTP and the branched-chain amino acids isoleucine, leucine, and valine (ILV). Additionally, small, regulatory RNAs (sRNAs) are emerging as important modulators of gene expression in S. aureus. My thesis focuses, in part, on furthering our understanding of the CodY regulon. In one case, I examined the impact of guanine nucleotides on S. aureus physiology and CodY activity. Blocking guanine nucleotide synthesis severely affects S. aureus fitness by altering metabolic and virulence gene expression. Second, I probed further into the CodY regulon by analyzing the extent to which CodY exerts its effect through small regulatory RNAs (sRNAs). Specifically, I characterized RsaD, a trans-acting sRNA that is important for fine-tuning carbon source utilization in S. aureus. My dissertation work outlines a complex regulatory network that includes both protein and RNA-based regulators that works to adjust S. aureus physiology in response to environmental and intracellular signals.