Like most cells, bacteria respond to adverse conditions by activating gene-expression pathways that increase their chances of survival. Such a pathway — the aptly named SOS response — is induced by genome damage or disruption of DNA replication, and results in the synthesis of DNA repair enzymes and the inhibition of bacterial cell division. Now, reporting in Science, Stanley N. Cohen and colleagues show that treatment of Escherichia coli with β-lactam antibiotics induces the SOS response, which decreases the lethal effects of these bactericidal drugs and enhances E. coli survival.

Previous studies have shown that overexpression of DpiA — the effector protein of the DpiBA two-component signal-transduction system in E. coli — inhibits DNA replication and therefore activates SOS-regulated genes. To characterize stimuli that activate the dpiBA operon, the authors transformed E. coli with a plasmid containing the dpiBA promoter fused to a lacZ reporter-gene fragment, and exposed these bacteria to various culture conditions. Suprisingly, Cohen and co-workers found that the β-lactam antibiotics — including ampicillin, cephalexin and pipericillin — induced expression of the dpi–lacZ reporter construct.

So what is the mechanism of dpiBA induction by β-lactam antibiotics? β-lactams bind to and inhibit the penicillin-binding proteins (PBPs). However, although ampicillin binds to all the PBPs, pipericillin and cephalexin bind to a specific PBP — PBP3. The authors therefore reasoned that inactivation of PBP3 might induce dpiBA expression. PBP3 is encoded by the temperature-sensitive ftsI gene and is required for the synthesis of the cell-wall septum that is formed during cell division. When ftsI was repressed by culture of E. coli at inhibitory temperatures, the marked increase in dpi–lacZ reporter-gene expression was comparable to that seen when the bacteria were exposed to ampicillin. Furthermore, a strain of E. coli that contained a lacZ reporter fused to an SOS-regulated promoter showed increased β-galactosidase synthesis on inhibition of the ftsI gene. This supports the hypothesis that defective septum synthesis caused by inactivation of PBP3 by β-lactams induces the SOS response.

The inhibition of cell division — an end-result of the SOS response — would allow microorganisms to 'shelter from antibiotic attack', as only dividing cells are vulnerable to the bactericidal effects of the β-lactams. This might contribute to bacterial persistence — a phenomenon in which small numbers of microorganisms survive despite antibiotic therapy. As the authors point out, the SOS response might therefore represent a novel therapeutic target “aimed at enhancing the efficacy of β-lactam antimicrobials”.