Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection
- 1 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 5 (2), 282-+
- https://doi.org/10.1038/s41564-019-0627-y
Abstract
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI133236, AI139304, AI119073, AI136920, R01AI137273, K22AI125501)
- Yang Biomedical Scholars Award
This publication has 44 references indexed in Scilit:
- A Genetic Resource for Rapid and Comprehensive Phenotype Screening of Nonessential Staphylococcus aureus GenesmBio, 2013
- Role of Oxidative Stress in Persister ToleranceAntimicrobial Agents and Chemotherapy, 2012
- Bacterial persistence increases as environmental fitness decreasesMicrobial Biotechnology, 2012
- A Common Mechanism of Cellular Death Induced by Bactericidal AntibioticsCell, 2007
- Francisella tularensis Replicates within Alveolar Type II Epithelial Cells In Vitro and In Vivo following InhalationInfection and Immunity, 2007
- Evaluation of the extracellular and intracellular activities (human THP-1 macrophages) of telavancin versus vancomycin against methicillin-susceptible, methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureusJournal of Antimicrobial Chemotherapy, 2006
- Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics against Staphylococcus aureus in a Model of THP-1 MacrophagesAntimicrobial Agents and Chemotherapy, 2006
- Staphylococcus aureusInfectionsThe New England Journal of Medicine, 1998
- STUDIES ON BACTERIEMIAThe Journal of Experimental Medicine, 1956
- The Antibacterial Action of Penicillin Against Gram Negative OrganismsScience, 1944