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Common and varied molecular responses of Escherichia coli to five different inhibitors of the lipopolysaccharide biosynthetic enzyme LpxC.
Möller, Anna-Maria; Vázquez-Hernández, Melissa; Kutscher, Blanka; Brysch, Raffael; Brückner, Simon; Marino, Emily C; Kleetz, Julia; Senges, Christoph H R; Schäkermann, Sina; Bandow, Julia E; Narberhaus, Franz.
Afiliación
  • Möller AM; Microbial Biology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Vázquez-Hernández M; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Kutscher B; Microbial Biology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Brysch R; Microbial Biology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Brückner S; Microbial Biology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Marino EC; Microbial Biology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Kleetz J; Microbial Biology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Senges CHR; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Schäkermann S; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Bandow JE; Applied Microbiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • Narberhaus F; Microbial Biology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany. Electronic address: franz.narberhaus@rub.de.
J Biol Chem ; 300(4): 107143, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38458396
ABSTRACT
A promising yet clinically unexploited antibiotic target in difficult-to-treat Gram-negative bacteria is LpxC, the key enzyme in the biosynthesis of lipopolysaccharides, which are the major constituents of the outer membrane. Despite the development of dozens of chemically diverse LpxC inhibitor molecules, it is essentially unknown how bacteria counteract LpxC inhibition. Our study provides comprehensive insights into the response against five different LpxC inhibitors. All compounds bound to purified LpxC from Escherichia coli. Treatment of E. coli with these compounds changed the cell shape and stabilized LpxC suggesting that FtsH-mediated proteolysis of the inactivated enzyme is impaired. LpxC inhibition sensitized E. coli to vancomycin and rifampin, which poorly cross the outer membrane of intact cells. Four of the five compounds led to an accumulation of lyso-phosphatidylethanolamine, a cleavage product of phosphatidylethanolamine, generated by the phospholipase PldA. The combined results suggested an imbalance in lipopolysaccharides and phospholipid biosynthesis, which was corroborated by the global proteome response to treatment with the LpxC inhibitors. Apart from LpxC itself, FabA and FabB responsible for the biosynthesis of unsaturated fatty acids were consistently induced. Upregulated compound-specific proteins are involved in various functional categories, such as stress reactions, nucleotide, or amino acid metabolism and quorum sensing. Our work shows that antibiotics targeting the same enzyme do not necessarily elicit identical cellular responses. Moreover, we find that the response of E. coli to LpxC inhibition is distinct from the previously reported response in Pseudomonas aeruginosa.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Escherichia coli / Amidohidrolasas Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Escherichia coli / Amidohidrolasas Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Alemania