Abstract
Bacterial chromosomes harbor toxin-antitoxin (TA) systems, some of which are implicated in the formation of multidrug-tolerant persister cells. In Escherichia coli, toxin TisB from the tisB/istR-1 TA system depolarizes the inner membrane and causes ATP depletion, which presumably favors persister formation. Transcription of tisB is induced upon DNA damage due to activation of the SOS response by LexA degradation. Transcriptional activation of tisB is counteracted on the post-transcriptional level by structural features of tisB mRNA and RNA antitoxin IstR-1. Deletion of the regulatory RNA elements (mutant Δ1-41 ΔistR) uncouples TisB expression from LexA-dependent SOS induction and causes a ‘high persistence’ (hip) phenotype upon treatment with different antibiotics. Here, we demonstrate by the use of fluorescent reporters that TisB overexpression in mutant Δ1-41 ΔistR inhibits cellular processes, including the expression of SOS genes. The failure in SOS gene expression does not affect the hip phenotype upon treatment with the fluoroquinolone ciprofloxacin, likely because ATP depletion avoids strong DNA damage. By contrast, Δ1-41 ΔistR cells are highly susceptible to the DNA cross-linker mitomycin C, likely because the expression of SOS-dependent repair systems is impeded. Hence, the hip phenotype of the mutant is conditional and strongly depends on the DNA-damaging agent.
Highlights
Bacteria are equipped with numerous systems to sense environmental stress factors and transduce the perceived stress signals into adequate responses
The hip phenotype of this mutant does not depend on SOS induction through LexA degradation, as shown by experiments with the non-cleavable LexA variant LexA3 [42]
Persister cells are marked by their ability to tolerate high levels of antibiotics and resume growth after the antibiotic treatment has ceased
Summary
Bacteria are equipped with numerous systems to sense environmental stress factors and transduce the perceived stress signals into adequate responses. These stress responses aim to repair the stress-induced damages, maintain essential cellular functions, and adjust the physiological status to the stressful situation. If stress levels are elevated, regular stress responses might not be sufficient to maintain survival For such fatal situations, bacteria have evolved survival strategies that are based on the formation of stress-tolerant cells through phenotypic variation [1,2]. Persister cells were first described in the 1940s [7,8], and are probably present in every bacterial population
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