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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.