# Understanding the role of arginine metabolism in antibiotic treatment failure during Staphylococcus aureus infections

> **NIH NIH K08** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $185,544

## Abstract

PROJECT SUMMARY
 Staphylococcus aureus is a leading cause of a wide range of bacterial infections globally and the most
common bacterial cause of mortality in the United States. These poor outcomes are driven by the high rates of
antibiotic treatment failure (15-40%) seen with many types of S. aureus infections including osteomyelitis,
prosthetic joint infections, and endocarditis. Antibiotic tolerance, which is defined as the ability of bacteria to
survive in the face of antibiotics through phenotypic changes without the acquisition of antibiotic resistance, is
the major driver of antibiotic treatment failure in S. aureus infections. Even with appropriate antibiotic therapy,
mortality rates can exceed 20% for some of these infections. Given the high incidence and the frequent treatment
failure, new and improved treatment options are needed to combat S. aureus infections.
 Despite the clinical significance of antibiotic tolerance, the mechanisms by which it occurs are poorly
understood. To gain new understanding of treatment failure in S. aureus infections, my fellowship research
focused on understanding antibiotic tolerance by conducting comprehensive, unbiased genetic and proteomic
screens of S. aureus during antibiotic exposure. With this approach, I identified a previously unknown relationship
between antibiotic tolerance and arginine metabolism where antibiotic tolerance in mature S. aureus
communities increases when arginine is depleted. In addition to being an essential amino acid for S. aureus
growth, arginine is also required for the production of nitric oxide by host immune cells such as neutrophils and
macrophages. Nitric oxide production is important for the host response to S. aureus infections, which
establishes arginine as an important contributor to the ability of the immune system to combat S. aureus.
Collectively, these results support the hypothesis that S. aureus influences arginine levels during infection by
carefully regulating arginine metabolism as a means to survive both in the face of antibiotics and the innate
immune response. Through this proposal, I plan to test this hypothesis by (1) elucidating the mechanism(s) by
which arginine metabolism influences antibiotic tolerance in S. aureus, (2) determining the role of S. aureus
arginine metabolism in persistence in the presence of innate immune effector cells, and (3) identifying the
contribution of S. aureus arginine metabolism to persistence and antibiotic treatment failure during infection.
Together, these experiments will better define the role of an essential amino acid at the host-pathogen interface.
The work in this proposal has the potential to uncover new therapeutics targets for the treatment of recalcitrant
infections that fail conventional therapies. In addition, through this award, I will receive important mentorship
while gaining specific research skills in animal models, eukaryotic cell culture, and imaging mass spectrometry.
This NIH K08 Mentored Clinical ...

## Key facts

- **NIH application ID:** 10948478
- **Project number:** 1K08AI185310-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jeffrey Alexander Freiberg
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $185,544
- **Award type:** 1
- **Project period:** 2024-08-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948478

## Citation

> US National Institutes of Health, RePORTER application 10948478, Understanding the role of arginine metabolism in antibiotic treatment failure during Staphylococcus aureus infections (1K08AI185310-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10948478. Licensed CC0.

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