Antibiotics of the β-lactam family inhibit the action of transpeptidases, essential enzymes that cross-link the peptidoglycan mesh. This inhibition halts peptidoglycan expansion and accounts for bacterial growth arrest. Binding of β-lactams on transpeptidases does not inhibit the action of glycosyltransferase enzymes, that polymerize new peptidoglycan strands, leading to a futile cycle of polymerization and hydrolysis of peptidoglycan synthesis intermediates. This futile cycle triggers a cell-wide metabolic dysregulation, causing global stresses that ultimately kill the bacterium. The aim of this research axis is to elucidate the cascade of events triggered by β-lactam binding to the transpeptidase targets. We use multi-omics approaches (Tn-seq, RNA-seq, Ribosome profiling, Metabolome and Proteome analyses) to identify all the regulatory circuits affected by β-lactam exposure and the significance of potential genome-wide gene expression dysregulation. This project aims to provide an exhaustive comprehension of the mechanism of β-lactam-induced bacterial death and will contribute to identifying new strategies to optimize the bactericidal activity of these antibiotics.

Associated publications:

• Voedts H, Anoyatis-Pelé C, Langella O, Rusconi F, Hugonnet JE, Arthur M. (2024). (p)ppGpp modifies RNAP function to confer β-lactam resistance in a peptidoglycan-independent manner. Nat Microbiol. Mar;9(3):647-656.
• Voedts, H., Kennedy, S.P., Sezonov, G., Arthur, M., and Hugonnet, J.E. (2022). Genome-wide identification of genes required for alternative peptidoglycan cross-linking in Escherichia coli revealed unexpected impacts of beta-lactams. Nat Commun 13, 7962.