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.

Notes

Originally published in PLoS Biology, 8(2): e1000317.
doi:10.1371/journal.pbio.1000317

This work was supported by grants 3R01 GM061162 and 3R01GM061162-10S1 from the National Institutes of Health (NIH) Institute of General Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

bacteria, persisters, stress response, toxin/antitoxin (TA) transcripts

Subject Categories

Antibiotics, Bacterial antitoxins, Bacterial toxins, Drug resistance in microorganisms, Ciprofloxacin

Disciplines

Bacteriology

Publisher

Public Library of Science Biology

Publication Date

2-23-2010

Rights Information

Copyright 2010. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Rights Holder

Tobias Dörr, Marin Vulić, Kim Lewis

Ciprofloxacin figure 1.tif (114 kB)
Figure S1: Persister formation in a strain with an istR-2 promoter deletion

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Additional Files

Ciprofloxacin figure 1.tif (114 kB)
Figure S1: Persister formation in a strain with an istR-2 promoter deletion

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