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The success of  Staphylococcus aureus  as a pathogen is due in part to its ability to adapt to changing environmental conditions using signal transduction pathways, such as metabolite- responsive regulators and two-component systems.  S .  aureus  has a two-component system encoded by the gene pair  sav 0224 ( hptS ) and  sav 0223 ( hptR ) that regulate the hexose phosphate transport ( uhpT)  system in response to extracellular glucose-6-phosphate. Glycolytic intermediates such as glucose-6-phosphate are important carbon sources that also modulate the activity of the global metabolite-responsive transcriptional regulator CcpA. Because  uhpT  has a putative CcpA binding site in its promoter and it is regulated by HptR, it was hypothesized the regulons of CcpA and HptR might intersect. To determine if the regulatory domains of CcpA and HptRS overlap,  ccpA  was deleted in strains SA564 and SA564-Δ hptRS  and growth, metabolic, proteomic, and transcriptional differences were assessed. As expected, CcpA represses  hptS  and  hptR  in a glucose dependent manner; however, upon CcpA derepression, the HptRS system functions as a transcriptional activator of metabolic genes within the CcpA regulon. Importantly, inactivation of  ccpA  and  hptRS  altered sensitivity to fosfomycin and ampicillin in the absence of exogenous glucose-6-phosphate, indicating that both CcpA and HptRS modulate antibiotic susceptibility.

Coordinated regulation of transcription by CcpA and the Staphylococcus aureus two-component system HptRS