title: Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells.
abstract: Prolonged antibiotic treatment can lead to detrimental side effects in patients, including ototoxicity, nephrotoxicity, and tendinopathy, yet the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. It has been suggested that bactericidal antibiotics induce the formation of toxic reactive oxygen species (ROS) in bacteria. We show that clinically relevant doses of bactericidal antibiotics-quinolones, aminoglycosides, and β-lactams-cause mitochondrial dysfunction and ROS overproduction in mammalian cells. We demonstrate that these bactericidal antibiotic-induced effects lead to oxidative damage to DNA, proteins, and membrane lipids. Mice treated with bactericidal antibiotics exhibited elevated oxidative stress markers in the blood, oxidative tissue damage, and up-regulated expression of key genes involved in antioxidant defense mechanisms, which points to the potential physiological relevance of these antibiotic effects. The deleterious effects of bactericidal antibiotics were alleviated in cell culture and in mice by the administration of the antioxidant N-acetyl-l-cysteine or prevented by preferential use of bacteriostatic antibiotics. This work highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people.
authors.affiliation: Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Kalghatgi
authors.affiliation: Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02215.|Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Spina
authors.affiliation: Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Costello
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.affiliation: Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: J Ruben
authors.initials: JR
authors.lastname: Morones-Ramirez
authors.affiliation: Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Shimyn
authors.initials: S
authors.lastname: Slomovic
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118.|Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27105, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Molina
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.affiliation: Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.|Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02215.|Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000617:Aminoglycosides / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D015363:Quinolones / Q000009:adverse effects / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D047090:beta-Lactams / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D015363:Quinolones; D017382:Reactive Oxygen Species; D047090:beta-Lactams; D013481:Superoxides; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide