Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 24, 2026.

A Primary Physiological Role of Toxin/Antitoxin Systems Is Phage Inhibition

Sooyeon Song, Thomas K. Wood

Frontiers in Microbiology · 2020 · Review · CC BY

doi:10.3389/fmicb.2020.01895

Abstract

Toxin/antitoxin (TA) systems are present in most prokaryote genomes. Toxins are almost exclusively proteins that reduce metabolism (but do not cause cell death), and antitoxins are either RNA or proteins that counteract the toxin or the RNA that encodes it. Although TA systems clearly stabilize mobile genetic elements, after four decades of research, the physiological roles of chromosomal TA systems are less clear. For example, recent reports have challenged the notion of TA systems as stress-response elements, including a role in creating the dormant state known as persistence. Here, we present evidence that a primary physiological role of chromosomally encoded TA systems is phage inhibition, a role that is also played by some plasmid-based TA systems. This includes results that show some CRISPR-Cas system elements are derived from TA systems and that some CRISPR-Cas systems mimic the host growth inhibition invoked by TA systems to inhibit phage propagation.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

Toxin/Antitoxin System Overview

Chromosomal toxin/antitoxin (TA) systems are prevalent in Bacteria and Archaea, and bacteria often have multiple members. For example, Escherichia coli K-12 has at least 39 TA systems. However, their role in cell physiology is disputed, even though it is highly unlikely they are merely addiction modules given their prevalence in most genomes and their redundancy. For this review, the phrase “chromosomal TA systems” excludes horizontally acquired genomic islands and active temperate phages but includes cryptic (inactive) prophages because they have been integrated into the host genome.

TA systems are encoded by adjacent genes, usually consisting of two components and usually result in the activation of a toxin that reduces metabolism. Contrary to much of the literature, toxins are probably not activated by specific degradation of bound antitoxins, which are structured and thereby not likely substrates of proteases such as Lon, but, instead, toxins are probably activated by de novo RNA synthesis. Toxins reduce metabolism in diverse ways, for example, by reducing ATP production by damaging the cell membrane, by inhibiting translation through mRNA/tRNA/rRNA modifications, and by impeding replication through adenylylation of DNA gyrase and topoisomerase IV.

TA systems are mobile through horizontal gene transfer, are often autoregulated, and may be arranged in cascades. There are eight classification groups for TA systems on the basis of the antitoxin mechanism: (i) antitoxin anti-sense RNA inhibits toxin mRNA in type I systems; (ii) antitoxin protein binds and inhibits toxin protein in type II systems; (iii) antitoxin RNA binds and inhibits the protein toxin in type III systems; (iv) antitoxin protein prevents the protein toxin from binding its target in type IV systems; (v) antitoxin enzyme, an RNase, degrades specifically toxin mRNA in type V systems; (vi) antitoxin protein stimulates the degradation of toxin protein in type VI systems; (vii) antitoxin enzyme oxidizes a cysteine residue of the protein toxin to inactivate it in type VII systems; and (viii) antitoxin RNA inactivates the toxin RNA by anti-sense binding, but the toxin functions as a small RNA rather than as a protein in type VIII systems.

Toxin/Antitoxin Systems Stabilize Mobile Genetic Elements

In contrast to chromosomally encoded TA systems, the physiological role of TA systems is more clear for mobile genetic elements like plasmids. The stabilization role was established with the discovery of TA systems via the report of the CcdB/CcdA type II TA system, which stabilizes the mini-F plasmid. Subsequently, the type I TA system, Hok/Sok, was shown to stabilize the R1 plasmid. Since these initial reports with plasmid stabilization, many examples of TA systems stabilizing plasmids have been documented. Furthermore, the integrative and conjugative element SXT in Vibrio cholerae has been shown to be stabilized via the MosT/MosA TA system, and TA systems stabilize prophages. Hence, although not all TA systems stabilize plasmids, the physiological role of TA systems for the stabilization of non-chromosomal mobile genetic elements is clear.

Toxin/Antitoxin Systems and the General Stress Response

Unlike the role of TA systems in stabilizing mobile genetic systems and in phage inhibition, the physiological role of chromosomal TA systems for stress resistance is being challenged. For example, the Van Melderen group published a series of negative results in which they claimed the chromosomal Escherichia coli MqsR/MqsA TA system had no role in stress resistance, on the basis of a lack of transcription response and lack of phenotype upon deleting mqsRA. Critically, their transcription results were invalidated within a few months in that mqsRA transcription was shown to increase by over 181-fold during amino acid stress and 90-fold during oxidative stress. In addition, although the Van Melderen group did not find a phenotype upon deleting mqsRA, including in the presence of bile acid stress, the Gross lab reported in Cell that E. coli mqsR has reduced growth with fusidic acid and radicicol, and they reported a hypomorphic mqsA mutation (i.e., a strain with reduced MqsA because mqsA is lethal owing to extreme MqsR toxicity; ) has reduced growth with the bile acid deoxycholate. Furthermore, we showed clearly that deleting mqsRA alters the cell’s response to bile acid in seven independent experiments with 2 to 5% deoxycholate and identified the importance of periplasmic protein YgiS as responsible for deoxycholate uptake. In addition, we discovered that antitoxin MqsA binds and represses the promoter of the master regulator of the stress response, sigma factor RpoS, through the palindrome that MqsA uses for its own transcription regulation; deletion of mqsRA along with five other TA systems increased both hydrogen peroxide and acid resistance by a factor of 10, and deletion of mqsRA increased biofilm formation, c-di-GMP levels, cellulose/curli. Also, three separate groups have found that MqsR/MqsA is related to antibiotic tolerance based upon deletion of mqsR. Convincingly, these results are based on deletions, rather than production of the TA module from plasmids.

In addition, other phenotypes have been reported that are related to the MqsR/MqsA TA system in E. coli, including those related to heat shock, biofilm formation, nitrogen starvation, and nitric oxide. Also, there are reported phenotypes related to the MqsR/MqsA TA system in non-E. coli systems including copper stress, vesicles, and biofilm formation in Xylella fastidiosa. Moreover, MqsR/MqsA affects biofilm formation in Pseudomonas fluorescens and persistence and biofilm formation in Pseudomonas putida. Similarly, other TA systems such as the MazE/MazF, RelE/RelB, and YafQ/DinJ TA systems have been linked to the general stress response; but their roles have also been disputed in E. coli.

In contrast to work showing chromosomal TA systems like MqsR/MqsA affect the stress response, the impact of TA systems on persistence is not convincing, primarily because the fold changes in most persister experiments with individual TA systems are usually small (less than 10-fold) and strains with multiple TA systems deleted do not show consistent phenotypes. Persistence is an extreme stress response that occurs when a subpopulation of cells becomes dormant due to ribosome dimerization as a direct result of increased ppGpp levels. Specifically, inactivation of 10 TA systems did not affect E. coli persistence for several groups. Similarly, deletion of 12 TA systems in Salmonella enterica had no effect on persistence.

In addition, there is little evidence that cells resuscitate by inactivating TA system toxins. For example, some have indicated that the peptidyl-tRNA hydrolase Pth counteracts toxin TacT in Salmonella Typhimurium during resuscitation; however, there are no data showing that Pth plays a role in persister resuscitation. Similarly, it was reported that deactivation of HokB toxin in E. coli causes persister cell resuscitation; however, single-cell observations were not used, the experiments rely on non-physiological levels of toxin from overproduction studies, deleting hokB has no effect on persistence, and GTPase Obg, the enzyme used to claim originally that HokB is related to persistence, reduces persistence without HokB. Therefore, although TA systems appear to be utilized by cells to respond to stress, they are probably not utilized to form or resuscitate persister cells.

Discovery of Toxin/Antitoxin Systems and Phage Inhibition

Restriction/modification systems are utilized to ward off phage infection; however, they also stabilize plasmids. Because TA systems stabilize plasmids, we reasoned by the transitive property that TA systems may also inhibit phage. In addition, we realized that temperature shock, amino acid deprivation, antibiotics, and, critically, phage infection, would alter transcription and would perhaps activate toxins of type I TA systems that rely on antisense antitoxin RNA production; hence, we hypothesized that TA systems may be used to inhibit phage. To test this hypothesis, we induced the type I TA system Hok/Sok from the R1 plasmid and challenged with T1, T4, T5, T7, and λ phage and found T4 phage were substantially inhibited: plating efficiency was reduced by 42%, plaque size was reduced by 85%, burst size was reduced by 40%, maturation time was increased by 36%, and the latent period was increased from 30 to 60 min. The likely mechanism is that upon phage infection, T4 phage blocks host transcription in 3–4 min, which leads to elimination of Hok and Sok RNA production; the Sok RNA is then preferentially degraded, and Hok toxin is produced. Therefore, a TA system was shown to inhibit phage. We also reasoned that phage inhibition by TA systems would be important for biofilms where cells in outer layers could protect kin.

Paradigm of Phage Inhibition and Toxin/Antitoxin Systems

Additional evidence of the role of TA systems for phage inhibition was provided 8 years later when it was shown the chromosomal type II MazF/MazE system inhibits phage P1. Critically, mazEF deletions produced more P1 phage; hence, the phenotype of phage exclusion was verified without overproducing this TA system. Also, the type II RnlA/RnlB system inhibits T4 phage in E. coli.

In addition, 13 years after the discovery of phage inhibition by Hok/sok, the type III ToxN/ToxI system from plasmid pECA1039 of phytopathogen Erwinia carotovora was found to inhibit phage φA2 and φM1 when produced from a plasmid, and 18 years later, the well-known abortive infection AbiEii/AbiEi system from plasmid pNP40 that inhibits the 936 phage family was suggested to be a type IV TA system. Hence, phage inhibition has been shown to be an important physiological role in types I, II, III, and IV TA systems.

Notably, in all TA systems tested for phage inhibition, there is no evidence of cell death during TA system activation under physiological conditions of toxin production, that is, via native toxin production levels. However, it is somewhat difficult to differentiate possible activation of a toxin during phage invasion that leads to cell killing and killing from the phage itself, except that if the toxin kills the cell, phage progeny would be reduced. Similarly, there is no evidence of cell death under physiological conditions of toxin production for plasmid stabilization. Hence, phrases like “post-segregational killing” and “programmed cell death” should be avoided because activation of toxins of TA systems serves to reduce metabolism, not kill cells (based on the evidence to date).

Phages Evolve Resistance to Phage Inhibition Systems

Phages and bacteria co-evolve to the extent that phages can be captured and utilized for the benefit of the host. Hence, phages have developed means to thwart host anti-phage mechanisms. For example, phages have evolved myriad ways to undermine both restriction/modification and CRISPR-Cas systems. Therefore, if TA systems are bona fide phage inhibition systems, there should be examples of phage systems that undermine host phage exclusion mechanisms. Critically, to thwart bacterial phage inhibition systems, phages now have been identified that include antitoxins in their genome to inhibit host toxins; for example, T4 phage carries the Dmd antitoxin that inactivates both the RnlA/RnlB and LsoA/IsoB type II TA systems of E. coli O157:H7. T4 phage Dmd inactivates toxin RnlA by direct binding. Similarly, the mycobacterium phage Ibhubesi encodes a homolog of McbA, the antitoxin of the MbcT–MbcA TA system of Mycobacterium tuberculosis.

As additional evidence of phage evolving resistance to host TA systems utilized for phage inhibition, T7 phage produces the protease inhibitor Gp4.5 to prevent activation of host TA systems by inhibiting Lon protease, which is used by many TA systems to degrade antitoxins. Hence, phage inhibition is an important physiological role of TA systems because four different types of TA systems inhibit phage and because phages have evolved defenses against TA systems.

In an additional role related to the co-evolution of phage and TA systems, whole, active TA systems have now been shown to be incorporated into phage genomes and used as regulatory units. Specifically, the PfiT/PfiA TA system is used by Pf4 filamentous phage of Pseudomonas aeruginosa to control phage production.

Malleable Toxin/Antitoxin Systems Evolved Into CRISPR-Cas Components

CRISPR-Cas is a prevalent anti-phage system present in about 40% of Bacteria and 90% of Archaea. The first link between TA systems and CRISPR-Cas was based on bioinformatics and linked Cas proteins to toxin VapD based on protein sequence homology. When we discovered the GhoT/GhoS type V TA system, the crystal structure of antitoxin GhoS linked it to Cas2 proteins of CRISPR-Cas, so another link between the two phage defense systems was established based on conservation of structure. TA systems are now considered the ancestors of Cas2 proteins. This evolution of TA systems into CRISPR-Cas systems is supported by random mutagenesis studies, which have shown antitoxins like GhoS (type V) can be converted into a novel toxin ArT via only two amino acid substitutions, and antitoxins like MqsA (type II) and ToxI (type III) can be made to inhibit this de novo toxin. This concept of TA system malleability has been confirmed.

CRISPR-Cas Systems Mimic Toxin/Antitoxin Systems by Utilizing Growth Inhibition for Phage Inhibition

Critically, upon detecting invading DNA, the type III CRISPR-Cas system of Streptococcus thermophilus degrades not only the invading DNA but also non-specific host RNA through cyclic oligoadenylate signaling modification of Csm6. In addition, the Staphylococcus epidermidis subtype III-A CRISPR-Cas system causes general host growth arrest (but not cell death) through Csm6 when plasmids invade with inefficient DNA targets. Hence, CRISPR-Cas in this species likely makes the host dormant to evade phage in a manner remarkably similar to TA systems, which reduce metabolism to limit phage propagation. Further evidence of general host arrest as an anti-phage response has been found in the Listeria seeligeri type VI-A CRISPR-Cas system, which uses Cas13 to degrade host RNA upon phage invasion; this CRISPR-Cas-induced host dormancy also protected neighboring cells from phage. Hence, inhibition of host metabolism by CRISPR-Cas systems is a common backup system to specific degradation of phage DNA, which mimics TA systems and their reduction in host growth to inhibit phage propagation. Moreover, it has been speculated that strains may utilize both CRISPR-Cas and TA systems for phage inhibition.

Perspectives

As summarized here, the most compelling arguments for phage inhibition as the primary physiological role of TA systems are (i) types I, II, III, and IV TA systems inhibit phage so this is a general mechanism; (ii) phages have evolved resistance to some bacterial TA phage exclusion systems to increase infection; and (iii) CRISPR-Cas systems, which are well-known phage inhibition strategies, mimic TA systems by reducing host metabolism to inhibit phage propagation.

Although the physiological role of phage inhibition by TA systems is well-established, to confirm phenotypes with new TA systems, we suggest that research should include experiments that show TA systems inhibit phage without over-producing the TA components; that is, TA loci should be deleted and the deletion strains tested for increased phage production. In this way, TA systems under physiological conditions will be further linked to phage inhibition.

Because phage attack is so prevalent, that is, there are 10-fold more phage than bacteria, perhaps the reason there are so many different TA systems in many bacterial genomes is not solely because of the various stresses bacteria encounter but also because different TA loci are utilized for different phages. Clearly, at this point in TA research, the answer to the question posed previously, “TA systems: why so many and what for”, is that, rather than “devoid of any current physiological role”, they are used for the epic battle between bacterium and phage, that is, specifically they are primarily used for phage inhibition.

Author Contributions

TW conceived and wrote the manuscript. SS helped writing the manuscript. Both authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 87

  1. 1.

    Aakre C. D. Herrou J. Phung T. N. Perchuk B. S. Crosson S. Laub M. T. (2015 ). Evolving new protein-protein interaction specificity through promiscuous intermediates. Cell 163 594–606.

    Not in our library10.1016/j.cell.2015.09.055

  2. 2.

    Aakre C. D. Phung T. N. Huang D. Laub M. T. (2013 ). A bacterial toxin inhibits DNA replication elongation through a direct interaction with the β sliding clamp. Mol. Cell. 52 617–628.

    Not in our library10.1016/j.molcel.2013.10.014

  3. 3.

    Bondy-Denomy J. Pawluk A. Maxwell K. L. Davidson A. R. (2013 ). Bacteriophage genes that inactivate the CRISPR/Cas bacterial immune system. Nature 493 429–432.

    Not in our library10.1038/nature11723

  4. 4.
    Three Dimensional Structure of the MqsR:MqsA Complex: A Novel TA Pair Comprised of a Toxin Homologous to RelE and an Antitoxin with Unique Properties · 2009
    No notice
  5. 5.

    Cheng H.-Y. Soo V. W. C. Islam S. McAnulty M. J. Benedik M. J. Wood T. K. (2014 ). Toxin GhoT of the GhoT/GhoS toxin/antitoxin system damages the cell membrane to reduce adenosine triphosphate and to reduce growth under stress. Environ. Microbiol. 16 1741–1754.

    Not in our library10.1111/1462-2920.12373

  6. 6.
    A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA · 2016
    No notice
  7. 7.

    Chibani-Chennoufi S. Bruttin A. Dillmann M.-L. Brüssow H. (2004 ). Phage-host interaction: an ecological perspective. J. Bacteriol. 186 3677–3686.

    Not in our library10.1128/jb.186.12.3677-3686.2004

  8. 8.

    Choi J. S. Kim W. Suk S. Park H. Bak G. Yoon J. (2018 ). The small RNA, SdsR, acts as a novel type of toxin in Escherichia coli. RNA Biol. 15 1319–1335.

    Not in our library10.1080/15476286.2018.1532252

  9. 9.

    Christensen S. K. Mikkelsen M. Pedersen K. Gerdes K. (2001 ). RelE, a global inhibitor of translation, is activated during nutritional stress. Proc. Natl. Acad. Sci. U.S.A. 98 14328–14333.

    Not in our library10.1073/pnas.251327898

  10. 10.

    Culviner P. H. Laub M. T. (2018 ). Global analysis of the E. coli toxin MazF reveals widespread cleavage of mRNA and the inhibition of rRNA maturation and ribosome biogenesis. Mol. Cell. 70 868.e10–880.e10.

    Not in our library10.1016/j.molcel.2018.04.026

  11. 11.

    Dewachter L. Fauvart M. Michiels J. (2019 ). Bacterial heterogeneity and antibiotic survival: understanding and combatting persistence and heteroresistance. Mol. Cell. 76 255–267.

    Not in our library10.1016/j.molcel.2019.09.028

  12. 12.
    A widespread bacteriophage abortive infection system functions through a Type IV toxin–antitoxin mechanism · 2014
    No notice
  13. 13.

    Figueira R. Brown D. R. Ferreira D. Eldridge M. J. G. Burchell L. Pan Z. (2015 ). Adaptation to sustained nitrogen starvation by Escherichia coli requires the eukaryote-like serine/threonine kinase YeaG. Sci. Rep. 5:17524.

    Not in our library10.1038/srep17524

  14. 14.

    Fineran P. C. Blower T. R. Foulds I. J. Humphreys D. P. Lilley K. S. Salmond G. P. C. (2009 ). The phage abortive infection system, ToxIN, functions as a protein–RNA toxin–antitoxin pair. Proc. Natl. Acad. Sci. U.S.A. 106 894–899.

    Not in our library10.1073/pnas.0808832106

  15. 15.

    Fraikin N. Rousseau C. J. Goeders N. Van Melderen L. (2019 ). Reassessing the Role of the Type II MqsRA toxin-antitoxin system in stress response and biofilm formation: mqsA is transcriptionally uncoupled from mqsR. mBio 10:e02678-19.

    Not in our library10.1128/mbio.02678-19

  16. 16.

    Freire D. M. Gutierrez C. Garza-Garcia A. Grabowska A. D. Sala A. J. Ariyachaokun K. (2019 ). An NAD+ phosphorylase toxin triggers Mycobacterium tuberculosis cell death. Mol. Cell. 73 1282.e8–1291.e8.

    Not in our library10.1016/j.molcel.2019.01.028

  17. 17.

    Gerdes K. Bech F. W. Jorgensen S. T. Lobner-Olesen A. Rasmussen P. B. Atlung T. (1986a ). Mechanism of postsegregational killing by the hok gene product of the parB system of plasmid R1 and its homology with the RelF gene product of the E. coli relB Operon. Eur. Mol. Biol. Organ. J. 5 2023–2029.

    Not in our library10.1002/j.1460-2075.1986.tb04459.x

  18. 18.

    Gerdes K. Rasmussen P. B. Molin S. (1986b ). Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells. Proc. Natl. Acad. Sci. U.S.A. 83 3116–3120.

    Not in our library10.1073/pnas.83.10.3116

  19. 19.
    Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of Escherichia coli Type II Persister Cells · 2018
    No notice
  20. 20.
    Prophages and Growth Dynamics Confound Experimental Results with Antibiotic-Tolerant Persister Cells · 2017
    No notice
  21. 21.

    Harms A. Stanger, Frédéric V. Scheu, Patrick D. de Jong (2015 ). Adenylylation of gyrase and topo IV by FicT toxins disrupts bacterial DNA topology. Cell Rep. 12 1497–1507.

    Not in our library10.1016/j.celrep.2015.07.056

  22. 22.

    Hazan R. Engelberg-Kulka H. (2004 ). Escherichia coli mazEF-mediated cell death as a defense mechanism that inhibits the spread of phage P1. Mol. Genet. Genomics 272 227–234.

    Not in our library10.1007/s00438-004-1048-y

  23. 23.

    Kazlauskiene M. Kostiuk G. Venclovas È Tamulaitis G. Siksnys V. (2017 ). A cyclic oligonucleotide signaling pathway in type III CRISPR-Cas systems. Science 357 605–609.

    Not in our library10.1126/science.aao0100

  24. 24.

    Kim J.-S. Wood T. K. (2016 ). Persistent persister misperceptions. Front. Microbiol. 7:2134.

    Not in our library10.3389/fmicb.2016.02134

  25. 25.

    Kim J.-S. Yamasaki R. Song S. Zhang W. Wood T. K. (2018 ). Single cell observations show persister cells wake based on ribosome content. Environ. Microbiol. 20 2085–2098.

    Not in our library10.1111/1462-2920.14093

  26. 26.

    Kim Y. Wood T. K. (2010 ). Toxins Hha and CspD and small RNA regulator Hfq are involved in persister cell formation through MqsR in Escherichia coli. Biochem. Biophys. Res. Commun. 391 209–213.

    Not in our library10.1016/j.bbrc.2009.11.033

  27. 27.

    Koga M. Otsuka Y. Lemire S. Yonesaki T. (2011 ). Escherichia coli rnlA and rnlB compose a novel toxin–antitoxin system. Genetics 187 123–130.

    Not in our library10.1534/genetics.110.121798

  28. 28.

    Kolodkin-Gal I. Hazan R. Gaathon A. Carmeli S. Engelberg-Kulka H. (2007 ). A linear pentapeptide is a quorum-sensing factor required for mazEF-mediated cell death in Escherichia coli. Science 318 652–655.

    Not in our library10.1126/science.1147248

  29. 29.

    Kulakauskas S. Lubys A. Ehrlich S. D. (1995 ). DNA restriction-modification systems mediate plasmid maintenance. J. Bacteriol. 177 3451–3454.

    Not in our library10.1128/jb.177.12.3451-3454.1995

  30. 30.

    Kwan B. W. Lord D. M. Peti W. Page R. Benedik M. J. Wood T. K. (2015 ). The MqsR/MqsA toxin/antitoxin system protects Escherichia coli during bile acid stress. Environ. Microbiol. 17 3168–3181.

    Not in our library10.1111/1462-2920.12749

  31. 31.

    Lee M. W. Tan C. C. Rogers E. E. Stenger D. C. (2014 ). Toxin-antitoxin systems mqsR/ygiT and dinJ/relE of Xylella fastidiosa. Physiol. Mol. Plant Pathol. 87 59–68.

    Not in our library10.1016/j.pmpp.2014.07.001

  32. 32.

    Lee Y. Song S. Sheng L. Zhu L. Kim J.-S. Wood T. K. (2018 ). Substrate binding protein DppA1 of ABC transporter DppBCDF increases biofilm formation in Pseudomonas aeruginosa by inhibiting Pf5 prophage lysis. Front. Microbiol. 9:30.

    Not in our library10.3389/fmicb.2018.00030

  33. 33.

    LeRoux M. Culviner P. H. Liu Y. J. Littlehale M. L. Laub M. T. (2020a ). Stress can induce transcription of toxin-antitoxin systems without activating toxin. Mol. Cell 79 280.e8–292.e8.

    Not in our library10.1016/j.molcel.2020.05.028

  34. 34.

    LeRoux M. Culviner P. H. Liu Y. J. Littlehale M. L. Laub M. T. (2020b ). Stress induces the transcription of toxin-antitoxin systems but does not activate toxin. bioRxiv [Preprint].

    Not in our library10.1101/2020.03.02.972737

  35. 35.

    Li Y. Liu X. Tang K. Wang W. Guo Y. Wang X. (2020 ). Prophage encoding toxin/antitoxin system PfiT/PfiA inhibits Pf4 production in Pseudomonas aeruginosa. Microb. Biotechnol. 13 1132–1144.

    Not in our library10.1111/1751-7915.13570

  36. 36.

    Luidalepp H. Jõers A. Kaldalu N. Tenson T. (2011 ). Age of inoculum strongly influences persister frequency and can mask effects of mutations implicated in altered persistence. J. Bacteriol. 193 3598–3605.

    Not in our library10.1128/jb.00085-11

  37. 37.
    A putative RNA-interference-based immune system in prokaryotes: computational analysis of the predicted enzymatic machinery, functional analogies with eukaryotic RNAi, and hypothetical mechanisms of action · 2006
    No notice
  38. 38.

    Makarova K. S. Wolf Y. I. Iranzo J. Shmakov S. A. Alkhnbashi O. S. Brouns S. J. J. (2020 ). Evolutionary classification of CRISPR–Cas systems: a burst of class 2 and derived variants. Nat. Rev. Microbiol. 18 67–83.

    Not in our library10.1038/s41579-019-0299-x

  39. 39.
    An oxygen-sensitive toxin–antitoxin system · 2016
    Not checked
  40. 40.

    Masuda H. Tan Q. Awano N. Wu K.-P. Inouye M. (2012 ). YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli. Mol. Microbiol. 84 979–989.

    Not in our library10.1111/j.1365-2958.2012.08068.x

  41. 41.

    Meeske A. J. Nakandakari-Higa S. Marraffini L. A. (2019 ). Cas13-induced cellular dormancy prevents the rise of CRISPR-resistant bacteriophage. Nature 570 241–245.

    Not in our library10.1038/s41586-019-1257-5

  42. 42.

    Merfa M. V. Niza B. Takita M. A. De Souza A. A. (2016 ). The MqsRA toxin-antitoxin system from Xylella fastidiosa plays a key role in bacterial fitness, pathogenicity, and persister cell formation. Front. Microbiol. 7:904.

    Not in our library10.3389/fmicb.2016.00904

  43. 43.

    Nichols R. J. Sen S. Choo Y. J. Beltrao P. Zietek M. Chaba R. (2011 ). Phenotypic landscape of a bacterial cell. Cell 144 143–156.

    Not in our library10.1016/j.cell.2010.11.052

  44. 44.

    Ogura T. Hiraga S. (1983 ). Mini-F plasmid genes that couple host cell division to plasmid proliferation. Proc. Natl. Acad. Sci. U.S.A. 80 4784–4788.

    Not in our library10.1073/pnas.80.15.4784

  45. 45.

    Otsuka Y. Yonesaki T. (2012 ). Dmd of bacteriophage T4 functions as an antitoxin against Escherichia coli LsoA and RnlA toxins. Mol. Microbiol. 83 669–681.

    Not in our library10.1111/j.1365-2958.2012.07975.x

  46. 46.

    Page R. Peti W. (2016 ). Toxin-antitoxin systems in bacterial growth arrest and persistence. Nat. Chem. Biol. 12:208.

    Not in our library10.1038/nchembio.2044

  47. 47.

    Partridge J. D. Bodenmiller D. M. Humphrys M. S. Spiro S. (2009 ). NsrR targets in the Escherichia coli genome: new insights into DNA sequence requirements for binding and a role for NsrR in the regulation of motility. Mol. Microbiol. 73 680–694.

    Not in our library10.1111/j.1365-2958.2009.06799.x

  48. 48.

    Pecota D. C. Wood T. K. (1996 ). Exclusion of T4 phage by the hok/sok killer locus from plasmid R1. J. Bacteriol. 178 2044–2050.

    Not in our library10.1128/jb.178.7.2044-2050.1996

  49. 49.

    Pontes M. H. Groisman E. A. (2019 ). Slow growth determines nonheritable antibiotic resistance in Salmonella enterica. Sci. Signal. 12:eaax3938.

    Not in our library10.1126/scisignal.aax3938

  50. 50.

    Ramisetty B. C. M. Santhosh R. S. (2015 ). Horizontal gene transfer of chromosomal Type II toxin–antitoxin systems of Escherichia coli. FEMS Microbiol. Lett. 363:fnv238.

    Not in our library10.1093/femsle/fnv238

  51. 51.

    Rauch B. J. Silvis M. R. Hultquist J. F. Waters C. S. McGregor M. J. Krogan N. J. (2017 ). Inhibition of CRISPR-Cas9 with bacteriophage proteins. Cell 168 150.e10–158.e10.

    Not in our library10.1016/j.cell.2016.12.009

  52. 52.

    Richmond C. S. Glasner J. D. Mau R. Jin H. Blattner F. R. (1999 ). Genome-wide expression profiling in Escherichia coli K-12. Nucleic Acids Res. 27 3821–3835.

    Not in our library10.1093/nar/27.19.3821

  53. 53.

    Rostøl J. T. Marraffini L. A. (2019a ). Non-specific degradation of transcripts promotes plasmid clearance during type III-A CRISPR–Cas immunity. Nat. Microbiol. 4 656–662.

    Not in our library10.1038/s41564-018-0353-x

  54. 54.

    Rostøl J. T. Marraffini L. A. (2019b ). Phighting phages: how bacteria resist their parasites. Cell Host Microbe 25 184–194.

    Not in our library10.1016/j.chom.2019.01.009

  55. 55.

    Saavedra De Bast M. Mine N. Van Melderen L. (2008 ). Chromosomal toxin-antitoxin systems may act as antiaddiction modules. J. Bacteriol. 190 4603–4609.

    Not in our library10.1128/jb.00357-08

  56. 56.

    Santiago A. D. S. Mendes J. S. Santos C. A. D. Toledo M. A. S. D. Beloti L. L. Crucello A. (2016 ). The antitoxin protein of a toxin-antitoxin system from Xylella fastidiosa is secreted via outer membrane vesicles. Front. Microbiol. 7:2030.

    Not in our library10.3389/fmicb.2016.02030

  57. 57.

    Sberro H. Leavitt A. Kiro R. Koh E. Peleg Y. Qimron U. (2013 ). Discovery of functional toxin/antitoxin systems in bacteria by shotgun cloning. Mol. Cell 50 136–148.

    Not in our library10.1016/j.molcel.2013.02.002

  58. 58.
    Persisters: a distinct physiological state of E. coli · 2006
    No notice
  59. 59.

    Song S. Guo Y. Kim J.-S. Wang X. Wood T. K. (2019 ). Phages mediate bacterial self recognition. Cell Rep. 27 737–749.

    Not in our library10.1016/j.celrep.2019.03.070

  60. 60.
    Post-segregational Killing and Phage Inhibition Are Not Mediated by Cell Death Through Toxin/Antitoxin Systems · 2018
    Not checked
  61. 61.

    Song S. Wood T. K. (2020a ). Persister cells resuscitate via ribosome modification by 23S rRNA Pseudouridine synthase RluD. Environ. Microbiol. 22 850–857.

    Not in our library10.1101/678425

  62. 62.

    Song S. Wood T. K. (2020b ). ppGpp ribosome dimerization model for bacterial persister formation and resuscitation. Biochem. Biophys. Res. Commun. 523 281–286.

    Not in our library10.1101/663658

  63. 63.

    Song S. Wood T. K. (2020c ). Toxin/antitoxin system paradigms: toxins bound to antitoxins are not likely activated by preferential antitoxin degradation. Adv. Biosyst. 4:1900290.

    Not in our library10.1002/adbi.201900290

  64. 64.

    Soo V. W. C. Cheng H.-Y. Kwan B. W. Wood T. K. (2014 ). de novo synthesis of a bacterial toxin/antitoxin system. Sci. Rep. 4:4807.

    Not in our library10.1038/srep04807

  65. 65.

    Sorek R. Kunin V. Hugenholtz P. (2008 ). CRISPR — a widespread system that provides acquired resistance against phages in bacteria and archaea. Nat. Rev. Microbiol. 6 181–186.

    Not in our library10.1038/nrmicro1793

  66. 66.

    Soutourina O. (2019 ). Type I toxin-antitoxin systems in clostridia. Toxins 11:253.

    Not in our library10.3390/toxins11050253

  67. 67.

    Stern A. Sorek R. (2011 ). The phage-host arms race: shaping the evolution of microbes. BioEssays 33 43–51.

    Not in our library10.1002/bies.201000071

  68. 68.

    Sun C. Guo Y. Tang K. Wen Z. Li B. Zeng Z. (2017 ). MqsR/MqsA toxin/antitoxin system regulates persistence and biofilm formation in Pseudomonas putida KT2440. Front. Microbiol. 8:840.

    Not in our library10.3389/fmicb.2017.00840

  69. 69.

    Svenningsen M. S. Veress A. Harms A. Mitarai N. Semsey S. (2019 ). Birth and resuscitation of (p)ppGpp induced antibiotic tolerant persister cells. Sci. Rep. 9:6056.

    Not in our library10.1038/s41598-019-42403-7

  70. 70.

    Tsilibaris V. Maenhaut-Michel G. Mine N. Van Melderen L. (2007 ). What is the benefit to Escherichia coli of having multiple toxin-antitoxin systems in its genome? J. Bacteriol. 189 6101–6108.

    Not in our library10.1128/jb.00527-07

  71. 71.

    Van Melderen L. (2010 ). Toxin-antitoxin systems: why so many, what for? Curr. Opin. Microbiol. 13 781–785.

    Not in our library10.1016/j.mib.2010.10.006

  72. 72.

    Verstraeten N. Knapen, Wouter J. Kint, Cyrielle I. Liebens V. (2015 ). Obg and membrane depolarization are part of a microbial bet-hedging strategy that leads to antibiotic tolerance. Mol. Cell. 59 9–21.

    Not in our library10.1016/j.molcel.2015.05.011

  73. 73.

    Wang X. Kim Y. Hong S. H. Ma Q. Brown B. L. Pu M. (2011 ). Antitoxin MqsA helps mediate the bacterial general stress response. Nat. Chem. Biol. 7 359–366.

    Not in our library10.1038/nchembio.560

  74. 74.

    Wang X. Kim Y. Ma Q. Hong S. H. Pokusaeva K. Sturino J. M. (2010 ). Cryptic prophages help bacteria cope with adverse environments. Nat. Commun. 1:147.

    Not in our library10.1038/ncomms1146

  75. 75.

    Wang X. Kim Y. Wood T. K. (2009 ). Control and benefits of CP4-57 prophage excision in Escherichia coli biofilms. ISME J. 3 1164–1179.

    Not in our library10.1038/ismej.2009.59

  76. 76.

    Wang X. Lord D. M. Cheng H.-Y. Osbourne D. O. Hong S. H. Sanchez-Torres V. (2012 ). A novel type V TA system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat. Chem. Biol. 8 855–861.

    Not in our library10.1038/nchembio.1062

  77. 77.

    Wang X. Lord D. M. Hong S. H. Peti W. Benedik M. J. Page R. (2013 ). Type II toxin/antitoxin MqsR/MqsA controls type V toxin/antitoxin GhoT/GhoS. Environ. Microbiol. 15 1734–1744.

    Not in our library10.1111/1462-2920.12063

  78. 78.

    Wang Y. Zhang S.-P. Zhang M.-Y. Kempher M. L. Guo D.-D. Han J.-T. (2019 ). The antitoxin MqsA homologue in Pseudomonas fluorescens 2P24 has a rewired regulatory circuit through evolution. Environ. Microbiol. 21 1740–1756.

    Not in our library10.1111/1462-2920.14538

  79. 79.

    Wei Y. Gao Z. Zhang H. Dong Y. (2016 ). Structural characterizations of phage antitoxin Dmd and its interactions with bacterial toxin RnlA. Biochem. Biophys. Res. Commun. 472 592–597.

    Not in our library10.1016/j.bbrc.2016.03.025

  80. 80.
    The Persistence-Inducing Toxin HokB Forms Dynamic Pores That Cause ATP Leakage · 2018
    Not checked
  81. 81.

    Wilmaerts D. Dewachter L. De Loose P.-J. Bollen C. Verstraeten N. Michiels J. (2019 ). HokB monomerization and membrane repolarization control persister awakening. Mol. Cell. 75 1031.e4–1042.e4.

    Not in our library10.1016/j.molcel.2019.06.015

  82. 82.

    Winther K. Tree J. J. Tollervey D. Gerdes K. (2016 ). VapCs of Mycobacterium tuberculosis cleave RNAs essential for translation. Nucleic Acids Res. 44 9860–9871.

    Not in our library10.1093/nar/gkw781

  83. 83.
    A Toxin–Antitoxin System Promotes the Maintenance of an Integrative Conjugative Element · 2009
    No notice
  84. 84.

    Wu N. He L. Cui P. Wang W. Yuan Y. Liu S. (2015 ). Ranking of persister genes in the same Escherichia coli genetic background demonstrates varying importance of individual persister genes in tolerance to different antibiotics. Front. Microbiol. 6:1003.

    Not in our library10.3389/fmicb.2015.01003

  85. 85.

    Yamaguchi Y. Park J. Inouye M. (2011 ). Toxin-antitoxin systems in bacteria and archaea. Annu. Rev. Genet. 45 61–79.

    Not in our library10.1146/annurev-genet-110410-132412

  86. 86.

    Yamasaki R. Song S. Benedik M. J. Wood T. K. (2020 ). Persister cells resuscitate using membrane sensors that activate chemotaxis, lower cAMP levels, and revive ribosomes. iScience 23:100792.

    Not in our library10.1016/j.isci.2019.100792

  87. 87.

    Zhao Y. McAnulty M. J. Wood T. K. (2016 ). Toxin YafQ reduces Escherichia coli growth at low temperatures. PLoS One 11:e0161577.

    Not in our library10.1371/journal.pone.0161577

Cited by papers we hold 3

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.