# The role of arginine catabolic pathways in modulating staphylococcal fitness

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $376,250

## Abstract

ABSTRACT
Despite decades of advances in clinical care, the high incidence of staphylococcal infections remain a major
public health concern. Multiple antibiotic-resistant isolates of Staphylococcus aureus and coagulase-negative
Staphylococcus epidermidis are frequently isolated in the hospital environment and significantly limit therapeutic
options. Indeed, it is increasingly becoming evident that a fundamental understanding of staphylococcal biology
and factors affecting its fitness are required for the development of effective therapeutics. Towards this goal, we
have recently identified important physiological functions for arginine catabolic enzymes including nitric oxide
synthase (NOS) and arginine deiminase (ADI), in promoting growth and controlling programmed cell death (PCD)
in staphylococci. Under normal physiological conditions, NOS activity promotes growth by activating respiration
and preventing metabolic dysfunction including excessive production of the polysaccharide intracellular adhesin
(PIA). However, influx of acetate (a byproduct of glucose metabolism) into the cytoplasm under acidic conditions
appears to corrupt normal function of NOS and promotes NOS-dependent production of reactive oxygen species
(ROS) and PCD. Interestingly, carbon flux through the ADI pathway appears to counter NOS-dependent PCD.
The mechanism by which these pathways affect staphylococcal physiology is still under intense investigation
and constitutes the subject of this application. In Aim #1, we will test how NOS promotes growth by suppressing
PIA production as part of its normal physiological activity. Further, we will investigate if phenylalanine plays a
role in NOS-dependent PIA suppression and whether NOS activity affects the pathogenic potential of
staphylococci using an infant mouse model of central nervous system (CNS) catheter infection. In Aim #2, we
will test the hypothesis that NOS-dependent ROS production during PCD results from NOS uncoupling, a
phenomenon wherein NOS generates superoxide rather than nitric oxide as byproduct. Finally in Aim #3, we will
test the potential for the arginine deiminase and the arginase pathways in countering PCD by activating catalase
activity through glutamate biosynthesis. On completion of these studies, we will gain a deeper mechanistic
understanding of how various arginine catabolic pathways affect staphylococcal physiology and fitness.

## Key facts

- **NIH application ID:** 10053306
- **Project number:** 5R01AI125588-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Vinai Thomas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,250
- **Award type:** 5
- **Project period:** 2017-11-06 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053306

## Citation

> US National Institutes of Health, RePORTER application 10053306, The role of arginine catabolic pathways in modulating staphylococcal fitness (5R01AI125588-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10053306. Licensed CC0.

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