The ratio between CcdA and CcdB modulates the transcriptional repression of the <i>ccd</i> poison–antidote system

Afif, Hassan; Allali, Noureddine; Couturier, Martine; Melderen, Laurence Van

doi:10.1046/j.1365-2958.2001.02492.x

Cited by 158 publications

(150 citation statements)

References 31 publications

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“…2). In both cases, it was observed that DNA binding of the CcdAB complex was decreased in the presence of excess 100TCcdB, as described previously for WT CcdB (14). It can also be seen that the complex of 100TCcdB with CcdA (lanes 6-8, Fig.…”

Section: Resultssupporting

confidence: 85%

“…In either event, the free WT CcdB could then bind to its cellular target, DNA gyrase, resulting in growth inhibition or cell death. Alternatively (or in addition), an increase in the CcdB:CcdA ratio as a result of mutant expression could lead to derepression of the ccd operon and fresh synthesis of CcdA and WT CcdB (14). The fresh CcdA would bind to the excess, inactive mutant of CcdB and the newly synthesized CcdB could bind to its cellular target, DNA gyrase.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

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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“…Under conditions of stress, the labile antitoxin is degraded. The resulting increase in the toxin/antitoxin ratio leads to transient derepression of the operon and fresh synthesis of both antitoxin and toxin (9). In the case of the ccdAB system on F-plasmidcontaining cells, the toxin CcdB is expressed along with its unstable antidote, CcdA, forming a TA complex.…”

Section: Abstract Toxin-antitoxin Persistencementioning

confidence: 99%

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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“…Cellular stress leads to an increase in toxin protein accumulation, most likely from antitoxin degradation. Specific toxin proteins such as RelE, Doc, and CcdA have been proposed to function as either transcriptional co-repressors, as part of the TA complex, or as de-repressors, which are dependent upon changes in the toxin-antitoxin ratios (25)(26)(27)(28)(29). Transcriptional de-repression is thought to occur by a mechanism in which excess toxin interacts with and destabilizes the TA-DNA repressor complex (25,26,29).…”

mentioning

confidence: 99%

Mechanisms of Toxin Inhibition and Transcriptional Repression by Escherichia coli DinJ-YafQ

Ruangprasert

Maehigashi

Miles

et al. 2014

Journal of Biological Chemistry

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Background: Toxin-antitoxin complexes autoregulate transcription depending upon growth conditions. Results: DinJ-YafQ structure was determined, and minimal requirements for transcriptional autorepression were identified. Conclusion:The dinJyafQ operon is regulated in a novel manner by either DinJ-YafQ-or LexA-mediated repression. Significance: Our results reveal new mechanistic insights into the action of DinJ-YafQ as a transcriptional repressor.

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The ratio between CcdA and CcdB modulates the transcriptional repression of the ccd poison–antidote system

Cited by 158 publications

References 31 publications

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

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

Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance

Mechanisms of Toxin Inhibition and Transcriptional Repression by Escherichia coli DinJ-YafQ

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