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 sepsis1. These more serious infections usually arise from an initial bloodstream infection and are frequently recalcitrant to antibiotic treatment1. Phagocytosis by macrophages and neutrophils is the primary mechanism through which S. aureus infection is controlled by the immune system2. Macrophages have been shown to be a major reservoir of S. aureus in vivo3, 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.

中文翻译：

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活性氧在全身金黄色葡萄球菌感染期间诱导抗生素耐受性。

金黄色葡萄球菌是一种主要的人类病原体，可引起一系列感染，从轻微的皮肤感染到更严重的感染，包括骨髓炎、心内膜炎、坏死性肺炎和败血症 1。这些更严重的感染通常是由最初的血流感染引起的，并且通常对抗生素治疗无效 1。巨噬细胞和中性粒细胞的吞噬作用是免疫系统控制金黄色葡萄球菌感染的主要机制2。巨噬细胞已被证明是体内金黄色葡萄球菌的主要储库3，但尚未探索巨噬细胞在诱导抗生素耐受性中的作用。在这里，我们表明巨噬细胞不仅不能有效杀死被吞噬的金黄色葡萄球菌，而且还会诱导对多种抗生素的耐受性。呼吸爆发产生的活性氧攻击含铁硫簇的蛋白质，包括 TCA 循环酶，导致呼吸减少、ATP 降低和抗生素耐受性增加。我们进一步表明，在小鼠全身感染期间，呼吸爆发会诱导脾脏对抗生素的耐受性。这些结果表明，先天免疫反应的主要组成部分对抗生素的杀菌活性具有拮抗作用。