Abstract
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 sav0224 (hptS) and sav0223 (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-ΔhptRS 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.
Highlights
Staphylococcus aureus is a common commensal bacterium and a versatile pathogen that can infect nearly any anatomic site
S. aureus strains were grown in tryptic soy broth (TSB) containing 0.25% dextrose (BD Biosciences), TSB without dextrose (TSB-dex; BD Biosciences), or on TSB containing 1.5% agar (TSA)
The growth of strains SA564 and SA564-ΔhptRS were equivalent when cultivated in TSB and TSB-dex (Fig 1A and 1B)
Summary
Staphylococcus aureus is a common commensal bacterium and a versatile pathogen that can infect nearly any anatomic site. The prevalence of S. aureus and its increasing antibiotic resistance contributed to a 50% increase in diagnoses from 9.17 to 13.79 per 1000 hospitalizations from 1999 to 2005 [4]. CcpA and HptRS co-regulation of transcription the success of S. aureus as a pathogen are strong indicators of its ability to adapt and survive in diverse conditions. S. aureus must be able to respond to changing environmental cues [5,6,7]. Rapid responses to environmental challenges are achieved by alterations in enzymatic activity and through transcriptional and translational initiation changes [6]. Feedback and feedforward enzymatic changes are induced by changes in substrate, cofactor, and/or inhibitor concentrations, while transcriptional and translational changes are mediated through metabolite, metal ion, and/or cofactor-responsive regulators (e.g., CcpA, Fur, Rex), small RNAs (e.g., RsaE), alternative sigma factors (e.g., σB), and two- or three-component regulators (e.g., KdpD-KdpE) [8,9,10,11,12,13,14,15,16,17]
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