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

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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.