title: Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage.
abstract: Understanding how antibiotics impact bacterial metabolism may provide insight into their mechanisms of action and could lead to enhanced therapeutic methodologies. Here, we profiled the metabolome of Escherichia coli after treatment with three different classes of bactericidal antibiotics (?-lactams, aminoglycosides, quinolones). These treatments induced a similar set of metabolic changes after 30 min that then diverged into more distinct profiles at later time points. The most striking changes corresponded to elevated concentrations of central carbon metabolites, active breakdown of the nucleotide pool, reduced lipid levels, and evidence of an elevated redox state. We examined potential end-target consequences of these metabolic perturbations and found that antibiotic-treated cells exhibited cytotoxic changes indicative of oxidative stress, including higher levels of protein carbonylation, malondialdehyde adducts, nucleotide oxidation, and double-strand DNA breaks. This work shows that bactericidal antibiotics induce a complex set of metabolic changes that are correlated with the buildup of toxic metabolic by-products.
authors.affiliation: Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA; Department of Molecular Microbiology and Immunology, Brown University, 171 Meeting Street, Providence, RI 02912, USA. Electronic address: peter_belenky@brown.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Belenky
authors.affiliation: Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ye
authors.affiliation: Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Caroline B M
authors.initials: CB
authors.lastname: Porter
authors.affiliation: Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Nadia R
authors.initials: NR
authors.lastname: Cohen
authors.affiliation: Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02115, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lobritz
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ferrante
authors.affiliation: Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Saloni
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Molecular Microbiology and Immunology, Brown University, 171 Meeting Street, Providence, RI 02912, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Korry
authors.affiliation: Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Schwarz
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Walker
authors.affiliation: Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA. Electronic address: jimjc@mit.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
mesh_terms: D000667:Ampicillin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004926:Escherichia coli / Q000187:drug effects*; D007612:Kanamycin / Q000494:pharmacology*; D009643:Norfloxacin / Q000494:pharmacology*; D018384:Oxidative Stress
chemical_list: D000900:Anti-Bacterial Agents; D007612:Kanamycin; D000667:Ampicillin; D009643:Norfloxacin
keywords: E. coli, metabolomics; antibiotics; double-strand breaks; lipid peroxidation; oxidative stress; protein carbonylation DNA damage; reactive oxygen species