Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage

Peter Belenky; Jonathan D Ye; Caroline B M Porter; Nadia R Cohen; Michael A Lobritz; Thomas Ferrante; Saloni Jain; Benjamin J Korry; Eric G Schwarz; Graham C Walker; James J Collins

doi:10.1016/j.celrep.2015.09.059

Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage

Cell Rep. 2015 Nov 3;13(5):968-80. doi: 10.1016/j.celrep.2015.09.059. Epub 2015 Oct 22.

Authors

Affiliations

¹ 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.
² Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA.
⁷ 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.
⁸ Department of Molecular Microbiology and Immunology, Brown University, 171 Meeting Street, Providence, RI 02912, USA.
⁹ Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
¹⁰ 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.

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.

Keywords: E. coli, metabolomics; antibiotics; double-strand breaks; lipid peroxidation; oxidative stress; protein carbonylation DNA damage; reactive oxygen species.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Ampicillin / pharmacology*
Anti-Bacterial Agents / pharmacology*
DNA Breaks, Double-Stranded
Escherichia coli / drug effects*
Kanamycin / pharmacology*
Norfloxacin / pharmacology*
Oxidative Stress*

Substances

Anti-Bacterial Agents
Kanamycin
Ampicillin
Norfloxacin

Abstract

Publication types

MeSH terms

Substances

Grants and funding