Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells
ABSTRACT Persistence is a reversible and low-frequency phenomenon allowing a subpopulation of a clonal bacterial population to survive antibiotic treatments. Upon removal of the antibiotic, persister cells resume growth and give rise to viable progeny. Type II toxin-antitoxin (TA) systems were assum...
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American Society for Microbiology
2018
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oai:doaj.org-article:2a24a6e8c67446f98d3a38d560a784c52021-11-15T16:00:26ZReassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells10.1128/mBio.00640-182150-7511https://doaj.org/article/2a24a6e8c67446f98d3a38d560a784c52018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00640-18https://doaj.org/toc/2150-7511ABSTRACT Persistence is a reversible and low-frequency phenomenon allowing a subpopulation of a clonal bacterial population to survive antibiotic treatments. Upon removal of the antibiotic, persister cells resume growth and give rise to viable progeny. Type II toxin-antitoxin (TA) systems were assumed to play a key role in the formation of persister cells in Escherichia coli based on the observation that successive deletions of TA systems decreased persistence frequency. In addition, the model proposed that stochastic fluctuations of (p)ppGpp levels are the basis for triggering activation of TA systems. Cells in which TA systems are activated are thought to enter a dormancy state and therefore survive the antibiotic treatment. Using independently constructed strains and newly designed fluorescent reporters, we reassessed the roles of TA modules in persistence both at the population and single-cell levels. Our data confirm that the deletion of 10 TA systems does not affect persistence to ofloxacin or ampicillin. Moreover, microfluidic experiments performed with a strain reporting the induction of the yefM-yoeB TA system allowed the observation of a small number of type II persister cells that resume growth after removal of ampicillin. However, we were unable to establish a correlation between high fluorescence and persistence, since the fluorescence of persister cells was comparable to that of the bulk of the population and none of the cells showing high fluorescence were able to resume growth upon removal of the antibiotic. Altogether, these data show that there is no direct link between induction of TA systems and persistence to antibiotics. IMPORTANCE Within a growing bacterial population, a small subpopulation of cells is able to survive antibiotic treatment by entering a transient state of dormancy referred to as persistence. Persistence is thought to be the cause of relapsing bacterial infections and is a major public health concern. Type II toxin-antitoxin systems are small modules composed of a toxic protein and an antitoxin protein counteracting the toxin activity. These systems were thought to be pivotal players in persistence until recent developments in the field. Our results demonstrate that previous influential reports had technical flaws and that there is no direct link between induction of TA systems and persistence to antibiotics.Frédéric GoormaghtighNathan FraikinMarta PutrinšThibaut HallaertVasili HauryliukAbel Garcia-PinoAndreas SjödinSergo KasvandikKlas UdekwuTanel TensonNiilo KaldaluLaurence Van MelderenAmerican Society for MicrobiologyarticleRelEYoeBampicillinsingle cellMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018) |
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RelE YoeB ampicillin single cell Microbiology QR1-502 |
| spellingShingle |
RelE YoeB ampicillin single cell Microbiology QR1-502 Frédéric Goormaghtigh Nathan Fraikin Marta Putrinš Thibaut Hallaert Vasili Hauryliuk Abel Garcia-Pino Andreas Sjödin Sergo Kasvandik Klas Udekwu Tanel Tenson Niilo Kaldalu Laurence Van Melderen Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells |
| description |
ABSTRACT Persistence is a reversible and low-frequency phenomenon allowing a subpopulation of a clonal bacterial population to survive antibiotic treatments. Upon removal of the antibiotic, persister cells resume growth and give rise to viable progeny. Type II toxin-antitoxin (TA) systems were assumed to play a key role in the formation of persister cells in Escherichia coli based on the observation that successive deletions of TA systems decreased persistence frequency. In addition, the model proposed that stochastic fluctuations of (p)ppGpp levels are the basis for triggering activation of TA systems. Cells in which TA systems are activated are thought to enter a dormancy state and therefore survive the antibiotic treatment. Using independently constructed strains and newly designed fluorescent reporters, we reassessed the roles of TA modules in persistence both at the population and single-cell levels. Our data confirm that the deletion of 10 TA systems does not affect persistence to ofloxacin or ampicillin. Moreover, microfluidic experiments performed with a strain reporting the induction of the yefM-yoeB TA system allowed the observation of a small number of type II persister cells that resume growth after removal of ampicillin. However, we were unable to establish a correlation between high fluorescence and persistence, since the fluorescence of persister cells was comparable to that of the bulk of the population and none of the cells showing high fluorescence were able to resume growth upon removal of the antibiotic. Altogether, these data show that there is no direct link between induction of TA systems and persistence to antibiotics. IMPORTANCE Within a growing bacterial population, a small subpopulation of cells is able to survive antibiotic treatment by entering a transient state of dormancy referred to as persistence. Persistence is thought to be the cause of relapsing bacterial infections and is a major public health concern. Type II toxin-antitoxin systems are small modules composed of a toxic protein and an antitoxin protein counteracting the toxin activity. These systems were thought to be pivotal players in persistence until recent developments in the field. Our results demonstrate that previous influential reports had technical flaws and that there is no direct link between induction of TA systems and persistence to antibiotics. |
| format |
article |
| author |
Frédéric Goormaghtigh Nathan Fraikin Marta Putrinš Thibaut Hallaert Vasili Hauryliuk Abel Garcia-Pino Andreas Sjödin Sergo Kasvandik Klas Udekwu Tanel Tenson Niilo Kaldalu Laurence Van Melderen |
| author_facet |
Frédéric Goormaghtigh Nathan Fraikin Marta Putrinš Thibaut Hallaert Vasili Hauryliuk Abel Garcia-Pino Andreas Sjödin Sergo Kasvandik Klas Udekwu Tanel Tenson Niilo Kaldalu Laurence Van Melderen |
| author_sort |
Frédéric Goormaghtigh |
| title |
Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells |
| title_short |
Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells |
| title_full |
Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells |
| title_fullStr |
Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells |
| title_full_unstemmed |
Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of <named-content content-type="genus-species">Escherichia coli</named-content> Type II Persister Cells |
| title_sort |
reassessing the role of type ii toxin-antitoxin systems in formation of <named-content content-type="genus-species">escherichia coli</named-content> type ii persister cells |
| publisher |
American Society for Microbiology |
| publishDate |
2018 |
| url |
https://doaj.org/article/2a24a6e8c67446f98d3a38d560a784c5 |
| work_keys_str_mv |
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