Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery

By Hongbaek Cho, T. Uehara, T. Bernhardt. Cell, 2014

603 citations recorded by the source corpus.

SUMMARY Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called penicillin-binding proteins (PBPs) that build the bacterial cell wall. Investigating the downstream consequences of target inhibition and how they contribute to the lethal action of these important drugs, we demonstrate that beta-lactams do more than just inhibit the PBPs as is commonly believed. Rather, they induce a toxic malfunctioning of their target biosynthetic machinery involving a futile cycle of cell wall synthesis and degradation, thereby depleting cellular resources and bolstering their killing activity. Characterization of this mode of action additionally revealed a quality-control function for enzymes that cleave bonds in the cell wall matrix. The results thus provide insight into the mechanism of cell wall assembly and suggest how best to interfere with the process for future antibiotic development.

Subfields: Genetics, Materials Chemistry, Molecular Medicine

View Paper: https://www.semanticscholar.org/paper/4981470e14a38b0892694162901a2f705f0469d7

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Citations in the corpus

Mechanisms of bacterial persistence during stress and antibiotic exposure (2016, background): “b-lactamantibiotics poison the cell wall synthesis machinery to induce a futile cycle of peptidoglycan synthesis and degradation that impairs cell wall integrity and results in osmotic lysis, particularly of growing cells (118).”
Persister formation in Staphylococcus aureus is associated with ATP depletion (2016, positive): “Aminoglycosides kill by causing mistranslation, which leads to the production of toxic peptides 29 ; fluoroquinolones inhibit the re-ligation step of DNA gyrase and topoisomerase, causing double strand breaks 30 , and β -lactams lead to a futile cycle of peptidoglycan synthesis and autolysis 31 .”
A white-box machine learning approach for revealing antibiotic mechanisms of action (2019, positive): “Additionally, futile cycling in cell wall synthesis and degradation was recently reported to be a component of b-lactam lethality (Cho et al., 2014).”