The identification of Staphylococcus aureus factors required for pathogenicity and growth in human blood

Staphylococcus aureus is a human commensal but also has devastating potential as an opportunist pathogen. S. aureus bacteraemia 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 on human blood. An ordered transposon mutant library was screened, identifying 9 genes involved specifically in haemolysis or growth on human blood agar compared 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 growth difference compared to the parental strain on human serum, human plasma, 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 enzyme ThyA and an 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 sulphonamide antibiotics.