Ciprofloxacin Causes Persister Formation by Inducing the TisB toxin in Escherichia coli

TLDR

Bacterial stress responses and persister formation are alternative survival strategies, with persisters being dormant, antibiotic‑tolerant cells whose formation mechanisms remain unclear but involve toxin/antitoxin transcripts. The study shows that the SOS‑induced toxin TisB drives ciprofloxacin‑triggered persister formation, and loss of the tisAB locus markedly reduces multidrug‑tolerant persisters.

Abstract

Bacteria induce stress responses that protect the cell from lethal factors such as DNA-damaging agents. Bacterial populations also form persisters, dormant cells that are highly tolerant to antibiotics and play an important role in recalcitrance of biofilm infections. Stress response and dormancy appear to represent alternative strategies of cell survival. The mechanism of persister formation is unknown, but isolated persisters show increased levels of toxin/antitoxin (TA) transcripts. We have found previously that one or more components of the SOS response induce persister formation after exposure to a DNA-damaging antibiotic. The SOS response induces several TA genes in Escherichia coli. Here, we show that a knockout of a particular SOS-TA locus, tisAB/istR, had a sharply decreased level of persisters tolerant to ciprofloxacin, an antibiotic that causes DNA damage. Step-wise administration of ciprofloxacin induced persister formation in a tisAB-dependent manner, and cells producing TisB toxin were tolerant to multiple antibiotics. TisB is a membrane peptide that was shown to decrease proton motive force and ATP levels, consistent with its role in forming dormant cells. These results suggest that a DNA damage–induced toxin controls production of multidrug tolerant cells and thus provide a model of persister formation.