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
Affiliations
Peter Belenky
Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA
Jonathan D. Ye
Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA
Caroline B.M. Porter
Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Nadia R. Cohen
Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Michael A. Lobritz
Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Thomas Ferrante
Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA 02115, USA
Saloni Jain
Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA
Benjamin J. Korry
Department of Molecular Microbiology and Immunology, Brown University, 171 Meeting Street, Providence, RI 02912, USA
Eric G. Schwarz
Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, 36 Cummington Mall, Boston, MA 02215, USA
Graham C. Walker
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
James J. Collins
Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
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 (β-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.
