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Transcriptional Regulators Coordinately Modulate Central Metabolism, Virulence, and Antibiotic Susceptibility of Staphylococcus aureus
Bacterial metabolism was initially studied in diverse genera and species yielding information on enzyme activity, flux, and enzymatic diversity. Upon the rise of “-omics” technologies, metabolic studies were primarily performed in the model organisms Escherichia coli and Bacillus subtilis, enriching the understanding of metabolic pathways and their regulation. However, not all phenotypically similar bacteria encode the same metabolic enzymes or regulatory systems. Renewed interest in researching the metabolism of non-model bacteria has been driven by the recognition that changes in bacterial metabolism are accompanied by changes in virulence factor production and antibiotic susceptibility. Hence, there is a need to investigate metabolism and its regulation in pathogenic bacteria such as Staphylococcus aureus, which causes hospital- and community-acquired infections and can be challenging to treat due to the emergence of antibiotic resistant strains. The success of S. aureus as a pathogen is due in part to signal transduction pathways, such as metabolite-responsive transcriptional regulators and two-component systems, which adapt gene transcription to changing environmental conditions. S. aureus has a two-component system (HptRS) encoded by the gene pair sav0224 (hptS) and sav0223 (hptR). HptRS is activated by extracellular glucose-6-phosphate and functions as a transcriptional regulator of uhpT which encodes a hexose phosphate transport protein. Glycolytic intermediates such as glucose-6-phosphate modulate the activity of the global transcriptional regulator carbon catabolite protein A (CcpA). Therefore, it was hypothesized that the regulon of HptRS likely overlaps with that of CcpA. To investigate this, ccpA was deleted in S. aureus strains SA564 and SA564-ΔhptRS and growth, metabolic, proteomic, and transcriptional differences were assessed. It was found that CcpA represses hptS and hptR in a glucose-dependent manner. However, upon CcpA deletion or de-repression the HptRS system functions as a transcriptional activator of metabolic and metabolite transport encoding genes within the CcpA regulon. This regulation was observed in medium with and without glucose, indicating that HptRS is activated by an additional signal independent of extracellular glucose-6-phosphate. Deletion of ccpA and hptRS also altered antibiotic sensitivity, indicating that transcriptional regulation by both CcpA and HptRS coordinately modulate metabolism and antibiotic susceptibility.
Reed, Joseph M, "Transcriptional Regulators Coordinately Modulate Central Metabolism, Virulence, and Antibiotic Susceptibility of Staphylococcus aureus" (2018). ETD collection for University of Nebraska - Lincoln. AAI10844177.