The Decay of the Chromosomally Encoded <i>ccdO157</i> Toxin–Antitoxin System in the <i>Escherichia coli</i> Species

Mine, Natacha; Guglielmini, Julien; Wilbaux, Myriam; Melderen, Laurence Van

doi:10.1534/genetics.108.095190

Cited by 42 publications

(57 citation statements)

References 34 publications

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“…A previous study indicated that chromosomally carried ccd operons undergo a decay process within the E. coli species and therefore are likely to lose their antiaddictive property, with about 29% of the strains harboring an inactive toxin (12). The present work suggests a probable explanation for the presence of an active ccd operon in more than 69% of the E. coli strains studied, namely, that they functionally integrate into the host regulatory network, leading to enhanced tolerance to multiple antibiotics through the formation of persisters.…”

Section: Discussionmentioning

confidence: 50%

“…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%

“…CcdB F , when expressed from the F plasmid, and CcdB O157 , when expressed from the E. coli chromosome, bind to the same target, gyrase A. However, they have been implicated in different functional roles (12,32,33). While the F-plasmid-carried ccd operon is involved in plasmid maintenance by postsegregational killing, no clear role has been attributed to the chromosomal ccd counterpart.…”

Section: Figmentioning

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: 50%

Section: Abstract Toxin-antitoxin Persistencementioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

et al. 2017

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“…ZP_01978533). The sequence of the chromosomal ccd systems have diverged significantly from the F-plasmid ccd operon studied here, although in ∼70% of cases both components of the chromosomal ccd have retained their toxic activity (26). Molecular evolutionary analysis of 47 isolates of ccdB 0157 suggested that the chromosomally encoded ccdAB TA systems appear devoid of any biological function and are under neutral evolution (26).…”

Section: Discussionmentioning

confidence: 82%

Additional role for the ccd operon of F-plasmid as a transmissible persistence factor

Tripathi

Dewan

Barua

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Toxin-antitoxin (TA) systems are found on both bacterial plasmids and chromosomes, but in most cases their functional role is unclear. Gene knockouts often yield limited insights into functions of individual TA systems because of their redundancy. The well-characterized F-plasmid–based CcdAB TA system is important for F-plasmid maintenance. We have isolated several point mutants of the toxin CcdB that fail to bind to its cellular target, DNA gyrase, but retain binding to the antitoxin, CcdA. Expression of such mutants is shown to result in release of the WT toxin from a functional preexisting TA complex as well as derepression of the TA operon. One such inactive, active-site mutant of CcdB was used to demonstrate the contribution of CcdB to antibiotic persistence. Transient activation of WT CcdB either by coexpression of the mutant or by antibiotic/heat stress was shown to enhance the generation of drug-tolerant persisters in a process dependent on Lon protease and RecA. An F-plasmid containing a ccd locus can, therefore, function as a transmissible persistence factor.

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“…Therefore, various chromosomal TAs may be the result of a specific arms race with their plasmid-encoded counterparts. However, when plasmidic TA systems 'escape' from this control (Saavedra De Bast et al, 2008;Mine et al, 2009;Rankin et al, 2012), the latter may undergo progressive degeneration and eventually disappear, unless they become incorporated into the cell's physiological processes, such as programmed cell death or persistence (Mine et al, 2009). …”

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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The Decay of the Chromosomally Encoded ccdO157 Toxin–Antitoxin System in the Escherichia coli Species

Cited by 42 publications

References 34 publications

Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

Additional role for the ccd operon of F-plasmid as a transmissible persistence factor

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

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