Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection

Staphylococcus aureus is a major human pathogen that causes an array of infections ranging from minor skin infections to more serious infections including osteomyelitis, endocarditis, necrotizing pneumonia and sepsis(1). These more serious infections usually arise from an initial bloodstream infection and are frequently recalcitrant to antibiotic treatment (1). Phagocytosis by macrophages and neutrophils is the primary mechanism by which S. aureus infection is controlled by the immune system(2). Macrophages have been shown to be a major reservoir of S. aureus in vivo(3) but the role of macrophages in the induction of antibiotic tolerance has not been explored. Here we show that macrophages not only fail to efficiently kill phagocytosed S. aureus but also induce tolerance to multiple antibiotics. Reactive oxygen species (ROS) generated by respiratory burst attack iron-sulfur (Fe-S) cluster containing proteins, including TCA cycle enzymes, resulting in decreased respiration, lower ATP and increased antibiotic tolerance. We further show that during a murine systemic infection, respiratory burst induces antibiotic tolerance in the spleen. These results suggest that a major component of the innate immune response is antagonistic to the bactericidal activities of antibiotics.