TisB Protein Protects Escherichia coli Cells Suffering Massive DNA Damage from Environmental Toxic Compounds

Toxin-antitoxin systems are genetic elements that are widespread in prokaryotes. Although molecular mode of action of many of these toxins has been identified, their biological functions are mostly unknown. We investigated the functional integration of the TisB/IstR toxin-antitoxin system in the Escherichia coli SOS genotoxic stress response network. We showed that the tisB gene is induced in cells exposed to high doses of the genotoxic antibiotic trimethoprim. However, we also found that TisB contributes to trimethoprim-induced lethality. This is a consequence of the TisB-induced drop in the proton motive force (PMF), which results in blocking the thymine import and therefore the functioning of the pyrimidine salvage pathway. Conversely, a TisB-induced PMF drop protects cells by preventing the import of some other toxic compounds, like the aminoglycoside antibiotic gentamicin and colicin M, in the SOS-induced cells. Colicins are cytotoxic molecules produced by Enterobacterales when they are exposed to strong genotoxic stresses in order to compete with other microbiota members. We indeed found that TisB contributes to E. coli’s fitness during mouse gut colonization. Based on the results obtained here, we propose that the primary biological role of the TisB toxin is to increase the probability of survival and maintenance in the mammalian gut of their bacterial hosts when they have to simultaneously deal with massive DNA damages and a fierce chemical warfare with other microbiota members.