EXAMINING HOST-DERIVED GLUTATHIONE AS A SULFUR SOURCE FOR STAPHYLOCOCCUS AUREUS DURING INFECTION

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus is a significant cause of morbidity and mortality due to the remarkable ability tocolonize multiple host tissues. Consistent with this, S. aureus is the leading cause of skin and soft tissueinfections, bacteremia, osteomyelitis and endocarditis. Treating these infections is challenging due to theprevalence of antibiotic resistant isolates, which necessitate the development of new therapeutic strategies. Toproliferate within diverse tissues, S. aureus acquires essential nutrients by exploiting abundant nutrient reservoirspresent in the host environment. S. aureus nutrient iron acquisition strategies have been studied for decades;however, the mechanisms employed by this pathogen to obtain the equally important nutrient sulfur duringinfection are not known. The sulfur-containing molecule, glutathione (GSH) is abundant in the host and supportsin vitro proliferation of S. aureus. Whether GSH satisfies the sulfur requirement during pathogenesis isunresolved. This is because we do not know how S. aureus imports or catabolizes GSH or derivatives thereof.To begin to elucidate the mechanisms S. aureus uses to acquire host-derived GSH, we took a genetic approachand identified five transposon-disrupted mutants that failed to grow in medium supplemented with GSH as thesole source of sulfur. Notably, the transposons mapped to an operon that encodes a putative ABC transporterand GSH degradation enzyme. Consequently, we renamed the operon the GSH import system or gisABCD-ggt.These preliminary data represent identification of the first sulfur source acquisition system in S. aureus, andsupport the hypothesis that the GisABCD-Ggt is system is required for S. aureus utilization of host-derivedGSH during infection. The proposed work will test this hypothesis by (i) defining the mechanisms that supportS. aureus to import and catabolize host-derived GSH, and (ii) establishing the importance of Gis-mediated GSHacquisition to S. aureus pathogenesis. Understanding how infection and the host immune response affects thechemical nature of GSH is also a goal of this proposal. The completion of these studies will reveal themechanisms S. aureus utilizes to acquire host-derived GSH during colonization of distinct tissues. This work hasthe potential to reveal a novel therapeutic strategy to combat antibiotic resistant S. aureus by impeding nutrientsulfur acquisition. We predict that the mechanism S. aureus employs to satisfy its sulfur requirement duringinfection is likely conserved in other bacterial pathogens, broadening the impact of the proposed work.