# Elucidating strategies of Staphylococcus aureus nutrient sulfur acquisition during infection

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $447,725

## Abstract

PROJECT SUMMARY/ABSTRACT
 Staphylococcus aureus is a significant cause of morbidity and mortality due to a remarkable capacity to
colonize multiple host tissues. Consistent with this, S. aureus is the leading cause of skin and soft tissue
infections, bacteremia, osteomyelitis and endocarditis. Treating infections can be exceedingly challenging due
to the prevalence of antibiotic resistant isolates, which necessitate the development of new therapeutic
strategies. To proliferate within diverse tissues, S. aureus acquires essential nutrients by exploiting abundant
nutrient reservoirs present 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 during infection are not known. Reduced and oxidized forms of the sulfur-containing molecules,
glutathione and cysteine, are abundant in host tissues and support in vitro proliferation of S. aureus. Whether
these molecules satisfy the sulfur requirement during pathogenesis is unresolved, because we do not understand
how S. aureus imports and catabolizes these molecules. To elucidate the mechanisms S. aureus employs to
acquire host-derived glutathione, we completed a forward genetic screen and identified mutants that fail to grow
in medium supplemented with glutathione as the sole source of sulfur. A reverse genetic approach was pursued
to identify potential cysteine transporters. We constructed mutants inactivated for homologues of putative
oxidized cysteine transporters and show that the mutated strains are impaired for oxidized cysteine utilization in
vitro. Notably, one of the importers provides a competitive advantage in liver colonization in a murine model of
systemic infection. These preliminary data represent identification of the first S. aureus sulfur acquisition systems
and support the hypothesis that during infection, S. aureus targets abundant host-derived sulfur-containing
molecules to satisfy the sulfur requirement. The proposed work will test this hypothesis by (i) establishing the
mechanisms that support S. aureus import and catabolism of host-derived GSH, (ii) identifying S. aureus reduced
and oxidized cysteine acquisition strategies during infection, and (iii) determining sulfur source abundance and
distribution at the host-pathogen interface. Understanding how the host immune response to infection impacts
sulfur source availability in tissues is also a goal of this study. The completion of this work will reveal the
mechanisms S. aureus employs to acquire host-derived sulfur sources during colonization of distinct tissues.
This work will provide novel therapeutic strategies to combat antibiotic resistant S. aureus by impeding nutrient
sulfur acquisition. We predict that S. aureus sulfur source acquisition strategies are likely conserved in other
bacterial pathogens, broadening the scope and impact of the proposed work.

## Key facts

- **NIH application ID:** 9857543
- **Project number:** 5R01AI139074-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Neal D. Hammer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,725
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857543

## Citation

> US National Institutes of Health, RePORTER application 9857543, Elucidating strategies of Staphylococcus aureus nutrient sulfur acquisition during infection (5R01AI139074-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857543. Licensed CC0.

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