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Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C

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 fo...

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Autores principales: Edelmann, Daniel, Leinberger, Florian H., Schmid, Nicole E., Oberpaul, Markus, Schäberle, Till F., Berghoff, Bork A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145889/
https://www.ncbi.nlm.nih.gov/pubmed/33925723
http://dx.doi.org/10.3390/microorganisms9050943
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author Edelmann, Daniel
Leinberger, Florian H.
Schmid, Nicole E.
Oberpaul, Markus
Schäberle, Till F.
Berghoff, Bork A.
author_facet Edelmann, Daniel
Leinberger, Florian H.
Schmid, Nicole E.
Oberpaul, Markus
Schäberle, Till F.
Berghoff, Bork A.
author_sort Edelmann, Daniel
collection PubMed
description 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.
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spelling pubmed-81458892021-05-26 Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C Edelmann, Daniel Leinberger, Florian H. Schmid, Nicole E. Oberpaul, Markus Schäberle, Till F. Berghoff, Bork A. Microorganisms Article 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. MDPI 2021-04-27 /pmc/articles/PMC8145889/ /pubmed/33925723 http://dx.doi.org/10.3390/microorganisms9050943 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Edelmann, Daniel
Leinberger, Florian H.
Schmid, Nicole E.
Oberpaul, Markus
Schäberle, Till F.
Berghoff, Bork A.
Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C
title Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C
title_full Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C
title_fullStr Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C
title_full_unstemmed Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C
title_short Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C
title_sort elevated expression of toxin tisb protects persister cells against ciprofloxacin but enhances susceptibility to mitomycin c
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145889/
https://www.ncbi.nlm.nih.gov/pubmed/33925723
http://dx.doi.org/10.3390/microorganisms9050943
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