Abstract
Induction of growth stasis by bacterial toxins from chromosomal toxin-antitoxin systems is suspected to favor formation of multidrug-tolerant cells, named persisters. Recurrent infections are often attributed to resuscitation and regrowth of persisters upon termination of antibiotic therapy. Several lines of evidence point to oxidative stress as a crucial factor during the persister life cycle. Here, we demonstrate that the membrane-depolarizing type I toxins TisB, DinQ, and HokB have the potential to provoke reactive oxygen species formation in Escherichia coli. More detailed work with TisB revealed that mainly superoxide is formed, leading to activation of the SoxRS regulon. Deletion of the genes encoding the cytoplasmic superoxide dismutases SodA and SodB caused both a decline in TisB-dependent persisters and a delay in persister recovery upon termination of antibiotic treatment. We hypothesize that expression of depolarizing toxins during the persister formation process inflicts an oxidative challenge. The ability to counteract oxidative stress might determine whether cells will survive and how much time they need to recover from dormancy.
Highlights
Induction of growth stasis by bacterial toxins from chromosomal toxin-antitoxin systems is suspected to favor formation of multidrug-tolerant cells, named persisters
We demonstrate that small hydrophobic proteins from type I TA systems have the potential to cause elevated levels of reactive oxygen species (ROS), and that the increase in ROS is consistent with the magnitude of toxin-induced depolarization (Fig. 1d,e)
It appears tempting to conclude that depolarization by pore-forming toxins represents a cellular disturbance that leads to ROS formation
Summary
Induction of growth stasis by bacterial toxins from chromosomal toxin-antitoxin systems is suspected to favor formation of multidrug-tolerant cells, named persisters. We demonstrate that the membrane-depolarizing type I toxins TisB, DinQ, and HokB have the potential to provoke reactive oxygen species formation in Escherichia coli. A reduction in persister levels by deletion of the toxin gene was so far only demonstrated for TisB upon treatment with DNA-damaging antibiotics[18,21], and remains to be tested for HokB and DinQ. Overexpression of several type I toxins in Escherichia coli caused increased mRNA levels of the oxidative stress regulator SoxS30. Transcription of soxS is induced by SoxR, a transcriptional regulator which is activated by redox-cycling drugs and superoxide[31,32] It remains, an outstanding question whether type I toxins have the potential to trigger ROS formation and how elevated ROS levels affect persister formation and recovery from the persister state
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