Chromosomal Toxin-Antitoxin Systems May Act as Antiaddiction Modules

Bast, Manuel Saavedra De; Mine, Natacha; Melderen, Laurence Van

doi:10.1128/jb.00357-08

Cited by 109 publications

(133 citation statements)

References 40 publications

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“…The antiaddiction model suggests that the presence of TA modules on the chromosome which can cross-react with a plasmidic or phage TA module could potentially give selective advantage to the plasmid-free cells by inhibiting postsegregational killing of cells that lose the plasmid (11). Mutations that are able to evade the antiaddiction will be selected by the plasmidic TA system, and vice versa for the chromosomally encoded TA system.…”

Section: Discussionmentioning

confidence: 99%

“…There are different models that have been proposed to explain their presence on the chromosome. For the chromosomal ccd systems, these include the antiaddiction model (11), which states that the chromosomally encoded ccd system (ccd Ech ) protects the cell against postsegregational killing mediated by its F-plasmid ccd (ccd F ) homolog, whereas for the ccd O157 system, it has been suggested that this system is devoid of any biological role in the E. coli species (12). Models proposed for other chromosomal TA systems include the programmed cell death (PCD) model, the growth modulation model, the persistence model, and the development model (13).…”

Section: Abstract Toxin-antitoxin Persistencementioning

confidence: 99%

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Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

et al. 2017

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One of the first identified and best-studied toxin-antitoxin (TA) systems in Escherichia coli is the F-plasmid-based CcdAB system. This system is involved in plasmid maintenance through postsegregational killing. More recently, ccdAB homologs have been found on the chromosome, including in pathogenic strains of E. coli and other bacteria. However, the functional role of chromosomal ccdAB genes, if any, has remained unclear. We show that both the native ccd operon of the E. coli O157 strain (ccd O157 ) and the ccd operon from the F plasmid (ccd F ), when inserted on the E. coli chromosome, lead to protection from cell death under multiple antibiotic stress conditions through formation of persisters, with the O157 operon showing higher protection. While the plasmid-encoded CcdB toxin is a potent gyrase inhibitor and leads to bacterial cell death even under fully repressed conditions, the chromosomally encoded toxin leads to growth inhibition, except at high expression levels, where some cell death is seen. This was further confirmed by transiently activating the chromosomal ccd operon through overexpression of an active-site inactive mutant of F-plasmid-encoded CcdB. Both the ccd F and ccd O157 operons may share common mechanisms for activation under stress conditions, eventually leading to multidrug-tolerant persister cells. This study clearly demonstrates an important role for chromosomal ccd systems in bacterial persistence.IMPORTANCE A large number of free-living and pathogenic bacteria are known to harbor multiple toxin-antitoxin systems, on plasmids as well as on chromosomes. The F-plasmid CcdAB system has been extensively studied and is known to be involved in plasmid maintenance. However, little is known about the function of its chromosomal counterpart, found in several pathogenic E. coli strains. We show that the native chromosomal ccd operon of the E. coli O157 strain is involved in drug tolerance and confers protection from cell death under multiple antibiotic stress conditions. This has implications for generation of potential therapeutics that target these TA systems and has clinical significance because the presence of persisters in an antibiotic-treated population can lead to resuscitation of chronic infection and may contribute to failure of antibiotic treatment.KEYWORDS toxin-antitoxin, persistence I n the early 1940s it was reported that a small fraction of staphylococcal cells, about one in a million, survived prolonged penicillin treatment (1). These cells were termed persisters. Later it was established that persisters are phenotypic variants in a given population that show antibiotic tolerance due to probable differences in their physiology under a given set of conditions. Upon subsequent culturing, they give rise to a population that retains antibiotic sensitivity. They are different from resistant cells in which resistance is genetically encoded and is passed on from one generation to the next. In contrast, persisters are transient and rare, ranging from 10 Ϫ2 to 10 Ϫ6 in frequenc...

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Section: Discussionmentioning

confidence: 99%

Section: Abstract Toxin-antitoxin Persistencementioning

confidence: 99%

Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

et al. 2017

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“…A multitude of theories as to the true purpose of TA systems have been proposed, especially to explain the physiological role of chromosomal TA systems (Gerdes et al 2005;Magnuson 2007;Saavedra De Bast et al 2008). One particularly interesting theory is that chromosomal TA systems act as anti-addiction mechanisms that prevent killing in the event of plasmid loss (Saavedra De Bast et al 2008). Chromosomal TA systems would thus drive the evolution of plasmid-encoded TA systems so that the toxins were no longer recognized by the anti-addiction modules.…”

Section: The World Of Conjugative Plasmidsmentioning

confidence: 99%

“…Their pervasiveness on plasmids and MGEs, however, is a testament to the vertical stability they offer any replicating elements that carry them. A multitude of theories as to the true purpose of TA systems have been proposed, especially to explain the physiological role of chromosomal TA systems (Gerdes et al 2005;Magnuson 2007;Saavedra De Bast et al 2008). One particularly interesting theory is that chromosomal TA systems act as anti-addiction mechanisms that prevent killing in the event of plasmid loss (Saavedra De Bast et al 2008).…”

Section: The World Of Conjugative Plasmidsmentioning

confidence: 99%

Conjugative plasmids: vessels of the communal gene pool

Norman

Hansen

Sørensen

2009

Phil. Trans. R. Soc. B

425

387

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Comparative whole-genome analyses have demonstrated that horizontal gene transfer (HGT) provides a significant contribution to prokaryotic genome innovation. The evolution of specific prokaryotes is therefore tightly linked to the environment in which they live and the communal pool of genes available within that environment. Here we use the term supergenome to describe the set of all genes that a prokaryotic 'individual' can draw on within a particular environmental setting. Conjugative plasmids can be considered particularly successful entities within the communal pool, which have enabled HGT over large taxonomic distances. These plasmids are collections of discrete regions of genes that function as 'backbone modules' to undertake different aspects of overall plasmid maintenance and propagation. Conjugative plasmids often carry suites of 'accessory elements' that contribute adaptive traits to the hosts and, potentially, other resident prokaryotes within specific environmental niches. Insight into the evolution of plasmid modules therefore contributes to our knowledge of gene dissemination and evolution within prokaryotic communities. This communal pool provides the prokaryotes with an important mechanistic framework for obtaining adaptability and functional diversity that alleviates the need for large genomes of specialized 'private genes'.

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“…Such degradation of chromosomal TAs may be discussed from the perspective of their anti-addiction function against plasmidic TAs, i.e. neutralization of a plasmid-encoded toxin to prevent the death of plasmid-free cells (Saavedra De Bast et al, 2008;Rankin et al, 2012). Therefore, various chromosomal TAs may be the result of a specific arms race with their plasmid-encoded counterparts.…”

Section: Q B Io S Y N T H E S Is P R O T E In H Y P O T H E T Ic a L mentioning

confidence: 99%

Type II toxin–antitoxin systems are unevenly distributed among Escherichia coli phylogroups

et al. 2015

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Type II toxin-antitoxin systems (TAs) are bicistronic operons ubiquitous in prokaryotic genomes, displaying multilevel association with cell physiology. Various possible functions have been assigned to TAs, ranging from beneficial for their hosts, such as a stress response, dormancy and protection against genomic parasites, to detrimental or useless functions, such as selfish alleles. As there is a link between several Escherichia coli features (e.g. virulence, lifestyle) and the phylogeny of this species, we hypothesized a similar association with TAs. Using PCR we studied the distribution of 15 chromosomal and plasmidic type II TA loci in 84 clinical E. coli isolates in relation to their main phylogenetic groups (A, B1, B2 and D). In addition, we performed in silico searching of these TA loci in 60 completely sequenced E. coli genomes deposited in GenBank. The highest number of TA loci per strain was observed in group A (mean 8.2, range 5-12) and the lowest in group B2 (mean 4.2, range 2-8). Moreover, significant differences in the prevalence of nine chromosomal TAs among E. coli phylogroups were noted. In conclusion, the presence of some chromosomal TAs in E. coli is phylogroup-related rather than a universal feature of the species. In addition, their limited collection in group B2 clearly distinguish it from the other E. coli phylogroups.

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Chromosomal Toxin-Antitoxin Systems May Act as Antiaddiction Modules

Cited by 109 publications

References 40 publications

Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

Conjugative plasmids: vessels of the communal gene pool

Type II toxin–antitoxin systems are unevenly distributed among Escherichia coli phylogroups

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