Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection

• Published in: Nature microbiology Vol. 5; no. 2; pp. 282 - 290
• Main Authors: Rowe, Sarah E., Wagner, Nikki J., Li, Lupeng, Beam, Jenna E., Wilkinson, Alec D., Radlinski, Lauren C., Zhang, Qing, Miao, Edward A., Conlon, Brian P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2020; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/51; 38; 38/35; 631/250/254; 631/326/22/1290; 631/326/41/2533; Animals; Antibiotic tolerance; Antibiotics; Biomedical and Life Sciences; Cell Line; Citric Acid Cycle; Disease Models, Animal; Disseminated infection; Drug Resistance, Bacterial - immunology; Endocarditis; Female; Host Microbial Interactions - immunology; Humans; Immune response; Immunity, Innate; Immunological tolerance; Infectious Diseases; Innate immunity; Iron; Letter; Leukocytes (neutrophilic); Life Sciences; Macrophages; Macrophages - immunology; Medical Microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; NADPH Oxidases - deficiency; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Neutrophils - immunology; Osteomyelitis; Parasitology; Penicillin; Phagocytosis; Reactive oxygen species; Reactive Oxygen Species - metabolism; Respiratory Burst; Spleen; Staphylococcal Infections - drug therapy; Staphylococcal Infections - immunology; Staphylococcal Infections - metabolism; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - genetics; Staphylococcus aureus - immunology; Staphylococcus infections; Sulfur; Virology
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-019-0627-y

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 through 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 generated by respiratory burst attack iron–sulfur cluster-containing proteins, including TCA-cycle enzymes, result in decreased respiration, lower ATP and increased antibiotic tolerance. We further show that respiratory burst induces antibiotic tolerance in the spleen during a murine systemic infection. These results suggest that a major component of the innate immune response is antagonistic to the bactericidal activities of antibiotics. Reactive oxygen species produced by macrophages following infection with Staphylococcus aureus attack bacterial iron–sulfur cluster-containing proteins, thereby leading to alterations in bacterial metabolism that increase their tolerance to antibiotics.