# The contribution of respiratory burst to antibiotic failure in Staphylococcus aureus bacteremia

> **NIH NIH R56** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $674,578

## Abstract

Summary Abstract
 Staphylococcus aureus infections are notoriously difficult to treat with antibiotics. Unlike many gram-
negative pathogens where the risk of treatment failure is associated with the increasing spread of antibiotic
resistance and the appearance of pan-resistant isolates, S. aureus remains largely susceptible to multiple
antibiotics. However, despite apparent susceptibility, these antibiotic treatments frequently fail, and 20,000
people died from S. aureus infections in the U.S in 2017.
 S. aureus are well-equipped to survive phagocytosis and the phagolysosome of macrophages is
increasingly appreciated as a major reservoir of S. aureus cells during infection. We find that, in a murine
model of systemic infection, S. aureus not only survives within macrophages but also enters into a multidrug
tolerant, persister state within this niche, rendering it untreatable with antibiotics.
Our overall hypothesis is that macrophage-S. aureus interactions are driving antibiotic treatment failure in
patients.
 To test this, in Aim 1, we will examine host macrophage induced antibiotic tolerance using clinical S.
aureus isolates and patient matched macrophages, cultured from peripheral blood mononuclear cells taken
from patients by Dr. Vance Fowler’s S. aureus bacteremia group (SABG). We will also examine if antibiotic
tolerance induction by macrophages in tissue culture can predict patient outcomes.
 In Aim 2, we will examine if respiratory burst is also capable of generating antibiotic resistant cells in
tissue culture and in a murine bacteremia model. The dual capacity of ROS produced by respiratory burst to
induce antibiotic tolerance and mutagenesis creates an ideal environment for the evolution of antibiotic
resistance during infection.
 In Aim 3, we will examine the potential of 2 therapeutic approaches to reduce antibiotic tolerance
induction by macrophages. Firstly, we will apply a series of antioxidants, including a state-of the art approach
involving the targeted delivery of therapeutics specifically to macrophages. Secondly, we will induce M2
polarization of macrophages to reduce ROS production and improve antibiotic susceptibility of phagocytosed
S. aureus.
 In all, our proposal promises to address the problem of S. aureus infection recalcitrance by identifying
the in vivo mechanism of persister formation in patients, examining how it contributes to antibiotic resistance
and identifying therapeutic approaches to inhibit the induction of persisters and improve the outcome of
antibiotic therapy.

## Key facts

- **NIH application ID:** 10666777
- **Project number:** 1R56AI158511-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Brian Patrick Conlon
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $674,578
- **Award type:** 1
- **Project period:** 2022-08-22 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10666777

## Citation

> US National Institutes of Health, RePORTER application 10666777, The contribution of respiratory burst to antibiotic failure in Staphylococcus aureus bacteremia (1R56AI158511-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10666777. Licensed CC0.

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