Genome-wide identification of genes required for alternative peptidoglycan cross-linking in Escherichia coli revealed unexpected impacts of β-lactams

Henri Voedts, Sean P. Kennedy, Guennadi Sezonov, Michel Arthur () and Jean-Emmanuel Hugonnet ()
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Henri Voedts: Sorbonne Université, Inserm, Université Paris Cité
Sean P. Kennedy: Institut Pasteur, Université Paris Cité, Département Biologie Computationnelle
Guennadi Sezonov: Sorbonne Université, Inserm, Université Paris Cité
Michel Arthur: Sorbonne Université, Inserm, Université Paris Cité
Jean-Emmanuel Hugonnet: Sorbonne Université, Inserm, Université Paris Cité

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The d,d-transpeptidase activity of penicillin-binding proteins (PBPs) is the well-known primary target of β-lactam antibiotics that block peptidoglycan polymerization. β-lactam-induced bacterial killing involves complex downstream responses whose causes and consequences are difficult to resolve. Here, we use the functional replacement of PBPs by a β-lactam-insensitive l,d-transpeptidase to identify genes essential to mitigate the effects of PBP inactivation by β-lactams in actively dividing bacteria. The functions of the 179 conditionally essential genes identified by this approach extend far beyond l,d-transpeptidase partners for peptidoglycan polymerization to include proteins involved in stress response and in the assembly of outer membrane polymers. The unsuspected effects of β-lactams include loss of the lipoprotein-mediated covalent bond that links the outer membrane to the peptidoglycan, destabilization of the cell envelope in spite of effective peptidoglycan cross-linking, and increased permeability of the outer membrane. The latter effect indicates that the mode of action of β-lactams involves self-promoted penetration through the outer membrane.

Date: 2022
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DOI: 10.1038/s41467-022-35528-3

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