# Examining host-derived glutathione as a sulfur source for Staphylococcus aureus during infection

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2020 · $193,750

## Abstract

PROJECT SUMMARY/ABSTRACT
 Staphylococcus aureus is a significant cause of morbidity and mortality due to the remarkable ability 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 these infections is 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. The sulfur-containing molecule, glutathione (GSH) is abundant in the host and supports
in vitro proliferation of S. aureus. Whether GSH satisfies the sulfur requirement during pathogenesis is
unresolved. 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 approach
and identified five transposon-disrupted mutants that failed to grow in medium supplemented with GSH as the
sole source of sulfur. Notably, the transposons mapped to an operon that encodes a putative ABC transporter
and 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, and
support the hypothesis that the GisABCD-Ggt is system is required for S. aureus utilization of host-derived
GSH during infection. The proposed work will test this hypothesis by (i) defining the mechanisms that support
S. aureus to import and catabolize host-derived GSH, and (ii) establishing the importance of Gis-mediated GSH
acquisition to S. aureus pathogenesis. Understanding how infection and the host immune response affects the
chemical nature of GSH is also a goal of this proposal. The completion of these studies will reveal the
mechanisms S. aureus utilizes to acquire host-derived GSH during colonization of distinct tissues. This work has
the potential to reveal a novel therapeutic strategy to combat antibiotic resistant S. aureus by impeding nutrient
sulfur acquisition. We predict that the mechanism S. aureus employs to satisfy its sulfur requirement during
infection is likely conserved in other bacterial pathogens, broadening the impact of the proposed work.

## Key facts

- **NIH application ID:** 9831125
- **Project number:** 5R21AI142517-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Neal D. Hammer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2018-12-03 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9831125

## Citation

> US National Institutes of Health, RePORTER application 9831125, Examining host-derived glutathione as a sulfur source for Staphylococcus aureus during infection (5R21AI142517-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9831125. Licensed CC0.

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