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Increased energy demand from anabolic-catabolic processes drives ß-lactam antibiotic lethality.
Lobritz, Michael A; Andrews, Ian W; Braff, Dana; Porter, Caroline B M; Gutierrez, Arnaud; Furuta, Yoshikazu; Cortes, Louis B G; Ferrante, Thomas; Bening, Sarah C; Wong, Felix; Gruber, Charley; Bakerlee, Christopher W; Lambert, Guillaume; Walker, Graham C; Dwyer, Daniel J; Collins, James J.
Afiliação
  • Lobritz MA; 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 MI
  • Andrews IW; 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 MI
  • Braff D; 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 Biomedi
  • Porter CBM; 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.
  • Gutierrez A; 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.
  • Furuta Y; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Cortes LBG; School of Applied and Engineering Physics, Cornell University, Ithaca, NY 14853, USA.
  • Ferrante T; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
  • Bening SC; 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.
  • Wong F; 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.
  • Gruber C; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Bakerlee CW; 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.
  • Lambert G; School of Applied and Engineering Physics, Cornell University, Ithaca, NY 14853, USA.
  • Walker GC; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Dwyer DJ; 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.
  • Collins JJ; 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 MI
Cell Chem Biol ; 29(2): 276-286.e4, 2022 02 17.
Article em En | MEDLINE | ID: mdl-34990601
ABSTRACT
ß-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 ß-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 ß-lactam antibiotics. Here, we assess the downstream metabolic consequences of treatment of Escherichia coli with the ß-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 ß-lactam antibiotic lethality.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Escherichia coli / Proteínas de Ligação às Penicilinas / Escherichia coli / Andinocilina / Antibacterianos Idioma: En Revista: Cell Chem Biol Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Escherichia coli / Proteínas de Ligação às Penicilinas / Escherichia coli / Andinocilina / Antibacterianos Idioma: En Revista: Cell Chem Biol Ano de publicação: 2022 Tipo de documento: Article