RRC ID 53581
Author Cho H, Uehara T, Bernhardt TG.
Title Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery.
Journal Cell
Abstract 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.
Volume 159(6)
Pages 1300-11
Published 2014-12-4
DOI 10.1016/j.cell.2014.11.017
PII S0092-8674(14)01448-2
PMID 25480295
PMC PMC4258230
MeSH Amdinocillin / pharmacology* Anti-Bacterial Agents / pharmacology* Cell Wall / drug effects Cell Wall / enzymology Escherichia coli / cytology Escherichia coli / drug effects* Escherichia coli / enzymology Glycoside Hydrolases / antagonists & inhibitors Penicillin-Binding Proteins / metabolism Peptidoglycan / metabolism beta-Lactams / pharmacology*
IF 38.637
Times Cited 197
Prokaryotes E. coli