Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality

Michael A Lobritz; Ian W Andrews; Dana Braff; Caroline B M Porter; Arnaud Gutierrez; Yoshikazu Furuta; Louis B G Cortes; Thomas Ferrante; Sarah C Bening; Felix Wong; Charley Gruber; Christopher W Bakerlee; Guillaume Lambert; Graham C Walker; Daniel J Dwyer; James J Collins

doi:10.1016/j.chembiol.2021.12.010

Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality

Cell Chem Biol. 2022 Feb 17;29(2):276-286.e4. doi: 10.1016/j.chembiol.2021.12.010. Epub 2022 Jan 5.

Authors

Michael A Lobritz¹, Ian W Andrews², Dana Braff³, Caroline B M Porter⁴, Arnaud Gutierrez⁴, Yoshikazu Furuta⁵, Louis B G Cortes⁶, Thomas Ferrante⁷, Sarah C Bening⁴, Felix Wong⁴, Charley Gruber⁸, Christopher W Bakerlee⁴, Guillaume Lambert⁶, Graham C Walker⁸, Daniel J Dwyer⁹, James J Collins¹⁰

Affiliations

¹ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
² Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
³ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
⁴ Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁵ Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ School of Applied and Engineering Physics, Cornell University, Ithaca, NY 14853, USA.
⁷ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁸ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁹ Department of Cell Biology and Molecular Genetics, Institute for Physical Science and Technology, Department of Biomedical Engineering, and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA. Electronic address: djdwyer@umd.edu.
¹⁰ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA. Electronic address: jimjc@mit.edu.

Abstract

β-Lactam antibiotics disrupt the assembly of peptidoglycan (PG) within the bacterial cell wall by inhibiting the enzymatic activity of penicillin-binding proteins (PBPs). It was recently shown that β-lactam treatment initializes a futile cycle of PG synthesis and degradation, highlighting major gaps in our understanding of the lethal effects of PBP inhibition by β-lactam antibiotics. Here, we assess the downstream metabolic consequences of treatment of Escherichia coli with the β-lactam mecillinam and show that lethality from PBP2 inhibition is a specific consequence of toxic metabolic shifts induced by energy demand from multiple catabolic and anabolic processes, including accelerated protein synthesis downstream of PG futile cycling. Resource allocation into these processes is coincident with alterations in ATP synthesis and utilization, as well as a broadly dysregulated cellular redox environment. These results indicate that the disruption of normal anabolic-catabolic homeostasis by PBP inhibition is an essential factor for β-lactam antibiotic lethality.

Keywords: antibiotic mechanism; antibiotics; bacterial metabolism; metabolomics; β-lactams.

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

Amdinocillin / chemistry
Amdinocillin / pharmacology*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Escherichia coli / drug effects*
Escherichia coli / metabolism
Escherichia coli Proteins / antagonists & inhibitors*
Escherichia coli Proteins / metabolism
Homeostasis / drug effects
Microbial Sensitivity Tests
Penicillin-Binding Proteins / antagonists & inhibitors*
Penicillin-Binding Proteins / metabolism

Substances

Anti-Bacterial Agents
Escherichia coli Proteins
Penicillin-Binding Proteins
MrdA protein, E coli
Amdinocillin

Abstract

Publication types

MeSH terms

Substances

Grants and funding