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

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. This is also true among Veterans, where S. aureus is a leading cause of many common infections and is associated with roughly one out of every 50 admissions to a VA hospital. Veterans are at increased risk of S. aureus infections due to the increased incidence of co- morbidities such as diabetes and renal failure, both of which have been shown to increase the risk and severity of S. aureus infections. In addition, diabetes and renal disease have been shown to increase the rates of recurrent S. aureus bacteremia specifically among Veterans. 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 of S. aureus infections, the frequent treatment failure, and the elevated risk for more severe outcomes among Veterans, 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 understand the mechanisms leading to 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. My preliminary experiments identified an increase in antibiotic tolerance in mature S. aureus communities 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. The importance of nitric oxide production to the host response to S. aureus infections, 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 targets for therapeutics to address the issue of treating recalcitrant infections that fail conventional therapies. In addition, through this Career Development Award, I will receive important mentorship while gaining specific research skills in animal models, eukaryotic cell culture, and imaging mass spectrometry. This VA CDA-2 will help me establish my own independent research program as part of my long-term goal of becoming a VA physician-scientist leader in the field of infectious diseases with an expertise in bacterial pathogenesis and antibiotic treatment failure. Project Number: 1IK2BX006543-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Jeffrey Freiberg | Institution: VETERANS HEALTH ADMINISTRATION, NASHVILLE, TN | Activity Code: IK2 | Study Section: Special Emphasis Panel[ZRD1 INFB-K (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11042348