Abstract
ABSTRACTStaphylococcus aureus is a human commensal but also has devastating potential as an opportunistic pathogen. S. aureus bacteremia is often associated with an adverse outcome. To identify potential targets for novel control approaches, we have identified S. aureus components that are required for growth in human blood. An ordered transposon mutant library was screened, and 9 genes involved specifically in hemolysis or growth on human blood agar were identified by comparing the mutants to the parental strain. Three genes (purA, purB, and pabA) were subsequently found to be required for pathogenesis in the zebrafish embryo infection model. The pabA growth defect was specific to the red blood cell component of human blood, showing no difference from the parental strain in growth in human serum, human plasma, or sheep or horse blood. PabA is required in the tetrahydrofolate (THF) biosynthesis pathway. The pabA growth defect was found to be due to a combination of loss of THF-dependent dTMP production by the ThyA enzyme and increased demand for pyrimidines in human blood. Our work highlights pabA and the pyrimidine salvage pathway as potential targets for novel therapeutics and suggests a previously undefined role for a human blood factor in the activity of sulfonamide antibiotics.
Highlights
Staphylococcus aureus is a human commensal and has devastating potential as an opportunistic pathogen
Strategies for overcoming the nutrient-limited environment in vivo have been well described for S. aureus and other bacteria; they include the upregulation of peptide or amino acid transport mechanisms [7] and of proteins that enable the acquisition of nutrients sequestered by the host [8, 9]
We show that purine biosynthesis is indispensable for growth on human blood and in vivo pathogenicity, using a zebrafish embryo model
Summary
Staphylococcus aureus is a human commensal and has devastating potential as an opportunistic pathogen. To identify potential targets for novel control approaches, we have identified S. aureus components that are required for growth in human blood. The pabA growth defect was found to be due to a combination of loss of THF-dependent dTMP production by the ThyA enzyme and increased demand for pyrimidines in human blood. Our work highlights pabA and the pyrimidine salvage pathway as potential targets for novel therapeutics and suggests a previously undefined role for a human blood factor in the activity of sulfonamide antibiotics. The pathogenicity of the Gram-positive bacterium Staphylococcus aureus requires a multitude of virulence factors that are intricately coordinated and regulated [1, 2]. Iai.asm.org 1 eration of Gram-positive pathogens on human blood [10], yet detailed studies of the growth requirements of S. aureus are lacking
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