Toxins, Targets, and Triggers: An Overview of Toxin-Antitoxin Biology

Molecular Cell

Volumn 70, Issue 5, 2018, Pages 768-784

  Harms, Alexander ^a   Brodersen, Ditlev Egeskov ^a,b   Mitarai, Namiko ^a,c   Gerdes, Kenn ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b AARHUS UNIVERSITY   (Denmark)

^c UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

abortive infection; antibiotic tolerance; bacterial persistence; conditional cooperativity; plasmid addiction; post segregational killing; RNA biology; toxin antitoxin modules

Indexed keywords

ANTITOXIN; BACTERIAL TOXIN; BACTERIAL PROTEIN; BACTERIAL RNA;

AUTOREGULATION; BIOLOGICAL ACTIVITY; BIOLOGICAL FUNCTIONS; HUMAN; MOLECULAR BIOLOGY; MOLECULAR EVOLUTION; NONHUMAN; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; TOXIN-ANTITOXIN SYSTEM; TRANSCRIPTION REGULATION; TRANSLATION REGULATION; ANTIBIOTIC RESISTANCE; BACTERIUM; CHEMISTRY; CONFORMATION; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; GENETICS; IMMUNOLOGY; INNATE IMMUNITY; METABOLISM; MICROBIAL VIABILITY; MOLECULAR MODEL; PATHOGENICITY; PROTEIN CONFORMATION; RNA PROCESSING; STRUCTURE ACTIVITY RELATION;

ANTITOXINS; BACTERIA; BACTERIAL PROTEINS; BACTERIAL TOXINS; DRUG RESISTANCE, BACTERIAL; EVOLUTION, MOLECULAR; GENE EXPRESSION REGULATION, BACTERIAL; IMMUNITY, INNATE; MICROBIAL VIABILITY; MODELS, MOLECULAR; NUCLEIC ACID CONFORMATION; PROTEIN CONFORMATION; RNA PROCESSING, POST-TRANSCRIPTIONAL; RNA, BACTERIAL; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTION, GENETIC;

EID: 85041590060     PISSN: 10972765     EISSN: 10974164     Source Type: Journal    
DOI: 10.1016/j.molcel.2018.01.003     Document Type: Review

References (133)

1. Aakre, C.D., Phung, T.N., Huang, D., Laub, M.T., A bacterial toxin inhibits DNA replication elongation through a direct interaction with the β sliding clamp. Mol. Cell 52 (2013), 617–628.
2. Afif, H., Allali, N., Couturier, M., Van Melderen, L., The ratio between CcdA and CcdB modulates the transcriptional repression of the ccd poison-antidote system. Mol. Microbiol. 41 (2001), 73–82.
3. Alawneh, A.M., Qi, D., Yonesaki, T., Otsuka, Y., An ADP-ribosyltransferase Alt of bacteriophage T4 negatively regulates the Escherichia coli MazF toxin of a toxin-antitoxin module. Mol. Microbiol. 99 (2016), 188–198.
4. Anantharaman, V., Aravind, L., New connections in the prokaryotic toxin-antitoxin network: relationship with the eukaryotic nonsense-mediated RNA decay system. Genome Biol., 4, 2003, R81.
5. Arbing, M.A., Handelman, S.K., Kuzin, A.P., Verdon, G., Wang, C., Su, M., Rothenbacher, F.P., Abashidze, M., Liu, M., Hurley, J.M., et al. Crystal structures of Phd-Doc, HigA, and YeeU establish multiple evolutionary links between microbial growth-regulating toxin-antitoxin systems. Structure 18 (2010), 996–1010.
6. Arnion, H., Korkut, D.N., Masachis Gelo, S., Chabas, S., Reignier, J., Iost, I., Darfeuille, F., Mechanistic insights into type I toxin antitoxin systems in Helicobacter pylori: the importance of mRNA folding in controlling toxin expression. Nucleic Acids Res. 45 (2017), 4782–4795.
7. Baharoglu, Z., Mazel, D., SOS, the formidable strategy of bacteria against aggressions. FEMS Microbiol. Rev. 38 (2014), 1126–1145.
8. Bendtsen, K.L., Xu, K., Luckmann, M., Winther, K.S., Shah, S.A., Pedersen, C.N.S., Brodersen, D.E., Toxin inhibition in C. crescentus VapBC1 is mediated by a flexible pseudo-palindromic protein motif and modulated by DNA binding. Nucleic Acids Res. 45 (2017), 2875–2886.
9. Berghoff, B.A., Wagner, E.G.H., RNA-based regulation in type I toxin-antitoxin systems and its implication for bacterial persistence. Curr. Genet. 63 (2017), 1011–1016.
10. Berghoff, B.A., Hoekzema, M., Aulbach, L., Wagner, E.G., Two regulatory RNA elements affect TisB-dependent depolarization and persister formation. Mol. Microbiol. 103 (2017), 1020–1033.
11. Bernard, P., Couturier, M., Cell killing by the F plasmid CcdB protein involves poisoning of DNA-topoisomerase II complexes. J. Mol. Biol. 226 (1992), 735–745.
12. Blower, T.R., Pei, X.Y., Short, F.L., Fineran, P.C., Humphreys, D.P., Luisi, B.F., Salmond, G.P., A processed noncoding RNA regulates an altruistic bacterial antiviral system. Nat. Struct. Mol. Biol. 18 (2011), 185–190.
13. Blower, T.R., Salmond, G.P., Luisi, B.F., Balancing at survival's edge: the structure and adaptive benefits of prokaryotic toxin-antitoxin partners. Curr. Opin. Struct. Biol. 21 (2011), 109–118.
14. Blower, T.R., Short, F.L., Rao, F., Mizuguchi, K., Pei, X.Y., Fineran, P.C., Luisi, B.F., Salmond, G.P., Identification and classification of bacterial type III toxin-antitoxin systems encoded in chromosomal and plasmid genomes. Nucleic Acids Res. 40 (2012), 6158–6173.
15. Bøggild, A., Sofos, N., Andersen, K.R., Feddersen, A., Easter, A.D., Passmore, L.A., Brodersen, D.E., The crystal structure of the intact E. coli RelBE toxin-antitoxin complex provides the structural basis for conditional cooperativity. Structure 20 (2012), 1641–1648.
16. Bordes, P., Sala, A.J., Ayala, S., Texier, P., Slama, N., Cirinesi, A.M., Guillet, V., Mourey, L., Genevaux, P., Chaperone addiction of toxin-antitoxin systems. Nat. Commun., 7, 2016, 13339.
17. Brown, J.M., Shaw, K.J., A novel family of Escherichia coli toxin-antitoxin gene pairs. J. Bacteriol. 185 (2003), 6600–6608.
18. Brown, B.L., Grigoriu, S., Kim, Y., Arruda, J.M., Davenport, A., Wood, T.K., Peti, W., Page, R., 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. PLoS Pathog., 5, 2009, e1000706.
19. Castro-Roa, D., Garcia-Pino, A., De Gieter, S., van Nuland, N.A.J., Loris, R., Zenkin, N., The Fic protein Doc uses an inverted substrate to phosphorylate and inactivate EF-Tu. Nat. Chem. Biol. 9 (2013), 811–817.
20. Cataudella, I., Trusina, A., Sneppen, K., Gerdes, K., Mitarai, N., Conditional cooperativity in toxin-antitoxin regulation prevents random toxin activation and promotes fast translational recovery. Nucleic Acids Res. 40 (2012), 6424–6434.
21. Cataudella, I., Sneppen, K., Gerdes, K., Mitarai, N., Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy. PLoS Comput. Biol., 9, 2013, e1003174.
22. Chan, W.T., Espinosa, M., Yeo, C.C., Keeping the wolves at bay: antitoxins of prokaryotic type II toxin-antitoxin systems. Front. Mol. Biosci., 3, 2016, 9.
23. Cheverton, A.M., Gollan, B., Przydacz, M., Wong, C.T., Mylona, A., Hare, S.A., Helaine, S., A Salmonella toxin promotes persister formation through acetylation of tRNA. Mol. Cell 63 (2016), 86–96.
24. Christensen, S.K., Gerdes, K., RelE toxins from bacteria and Archaea cleave mRNAs on translating ribosomes, which are rescued by tmRNA. Mol. Microbiol. 48 (2003), 1389–1400.
25. Christensen-Dalsgaard, M., Jørgensen, M.G., Gerdes, K., Three new RelE-homologous mRNA interferases of Escherichia coli differentially induced by environmental stresses. Mol. Microbiol. 75 (2010), 333–348.
26. Coray, D.S., Wheeler, N.E., Heinemann, J.A., Gardner, P.P., Why so narrow: distribution of anti-sense regulated, type I toxin-antitoxin systems compared with type II and type III systems. RNA Biol. 14 (2017), 275–280.
27. Dalton, K.M., Crosson, S., A conserved mode of protein recognition and binding in a ParD-ParE toxin-antitoxin complex. Biochemistry 49 (2010), 2205–2215.
28. Darfeuille, F., Unoson, C., Vogel, J., Wagner, E.G., An antisense RNA inhibits translation by competing with standby ribosomes. Mol. Cell 26 (2007), 381–392.
29. De Jonge, N., Garcia-Pino, A., Buts, L., Haesaerts, S., Charlier, D., Zangger, K., Wyns, L., De Greve, H., Loris, R., Rejuvenation of CcdB-poisoned gyrase by an intrinsically disordered protein domain. Mol. Cell 35 (2009), 154–163.
30. Deane, S.M., Rawlings, D.E., Plasmid evolution and interaction between the plasmid addiction stability systems of two related broad-host-range IncQ-like plasmids. J. Bacteriol. 186 (2004), 2123–2133.
31. Dienemann, C., Bøggild, A., Winther, K.S., Gerdes, K., Brodersen, D.E., Crystal structure of the VapBC toxin-antitoxin complex from Shigella flexneri reveals a hetero-octameric DNA-binding assembly. J. Mol. Biol. 414 (2011), 713–722.
32. Dörr, T., Lewis, K., Vulić M., SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genet., 5, 2009, e1000760.
33. Dörr, T., Vulić M., Lewis, K., Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol., 8, 2010, e1000317.
34. Dy, R.L., Przybilski, R., Semeijn, K., Salmond, G.P., Fineran, P.C., A widespread bacteriophage abortive infection system functions through a Type IV toxin-antitoxin mechanism. Nucleic Acids Res. 42 (2014), 4590–4605.
35. Dy, R.L., Richter, C., Salmond, G.P., Fineran, P.C., Remarkable mechanisms in microbes to resist phage infections. Annu. Rev. Virol. 1 (2014), 307–331.
36. Feng, J., Kessler, D.A., Ben-Jacob, E., Levine, H., Growth feedback as a basis for persister bistability. Proc. Natl. Acad. Sci. USA 111 (2014), 544–549.
37. Fineran, P.C., Blower, T.R., Foulds, I.J., Humphreys, D.P., Lilley, K.S., Salmond, G.P., The phage abortive infection system, ToxIN, functions as a protein-RNA toxin-antitoxin pair. Proc. Natl. Acad. Sci. USA 106 (2009), 894–899.
38. Fozo, E.M., Makarova, K.S., Shabalina, S.A., Yutin, N., Koonin, E.V., Storz, G., Abundance of type I toxin-antitoxin systems in bacteria: searches for new candidates and discovery of novel families. Nucleic Acids Res. 38 (2010), 3743–3759.
39. Franch, T., Gerdes, K., Programmed cell death in bacteria: translational repression by mRNA end-pairing. Mol. Microbiol. 21 (1996), 1049–1060.
40. Garcia-Pino, A., Balasubramanian, S., Wyns, L., Gazit, E., De Greve, H., Magnuson, R.D., Charlier, D., van Nuland, N.A., Loris, R., Allostery and intrinsic disorder mediate transcription regulation by conditional cooperativity. Cell 142 (2010), 101–111.
41. Gelens, L., Hill, L., Vandervelde, A., Danckaert, J., Loris, R., A general model for toxin-antitoxin module dynamics can explain persister cell formation in E. coli. PLoS Comput. Biol., 9, 2013, e1003190.
42. Gerdes, K., Hypothesis: type I toxin-antitoxin genes eneter the persistence field–a feedback mechanism explaining membrane homeostasis. Philos. Trans. R. Soc. Lond. B Biol. Sci., 371, 2016, 20160189.
43. Gerdes, K., Bech, F.W., Jørgensen, S.T., Løbner-Olesen, A., Rasmussen, P.B., Atlung, T., Boe, L., Karlstrom, O., Molin, S., von Meyenburg, K., 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. EMBO J. 5 (1986), 2023–2029.
44. Gerdes, K., Rasmussen, P.B., Molin, S., Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells. Proc. Natl. Acad. Sci. USA 83 (1986), 3116–3120.
45. Gerdes, K., Helin, K., Christensen, O.W., Løbner-Olesen, A., Translational control and differential RNA decay are key elements regulating postsegregational expression of the killer protein encoded by the parB locus of plasmid R1. J. Mol. Biol. 203 (1988), 119–129.
46. Germain, E., Castro-Roa, D., Zenkin, N., Gerdes, K., Molecular mechanism of bacterial persistence by HipA. Mol. Cell 52 (2013), 248–254.
47. Goeders, N., Van Melderen, L., Toxin-antitoxin systems as multilevel interaction systems. Toxins (Basel) 6 (2014), 304–324.
48. Goeders, N., Chai, R., Chen, B., Day, A., Salmond, G.P., Structure, evolution, and functions of bacterial type III toxin-antitoxin systems. Toxins (Basel), 8, 2016, E282.
49. Gotfredsen, M., Gerdes, K., The Escherichia coli relBE genes belong to a new toxin-antitoxin gene family. Mol. Microbiol. 29 (1998), 1065–1076.
50. Grønlund, H., Gerdes, K., Toxin-antitoxin systems homologous with relBE of Escherichia coli plasmid P307 are ubiquitous in prokaryotes. J. Mol. Biol. 285 (1999), 1401–1415.
51. Guglielmini, J., Van Melderen, L., Bacterial toxin-antitoxin systems: translation inhibitors everywhere. Mob. Genet. Elements 1 (2011), 283–290.
52. Guo, Y., Quiroga, C., Chen, Q., McAnulty, M.J., Benedik, M.J., Wood, T.K., Wang, X., RalR (a DNase) and RalA (a small RNA) form a type I toxin-antitoxin system in Escherichia coli. Nucleic Acids Res. 42 (2014), 6448–6462.
53. Hall, A.M., Gollan, B., Helaine, S., Toxin-antitoxin systems: reversible toxicity. Curr. Opin. Microbiol. 36 (2017), 102–110.
54. Hallez, R., Geeraerts, D., Sterckx, Y., Mine, N., Loris, R., Van Melderen, L., New toxins homologous to ParE belonging to three-component toxin-antitoxin systems in Escherichia coli O157:H7. Mol. Microbiol. 76 (2010), 719–732.
55. Hargreaves, D., Santos-Sierra, S., Giraldo, R., Sabariegos-Jareño, R., de la Cueva-Méndez, G., Boelens, R., Díaz-Orejas, R., Rafferty, J.B., Structural and functional analysis of the kid toxin protein from E. coli plasmid R1. Structure 10 (2002), 1425–1433.
56. Harms, A., Stanger, F.V., Scheu, P.D., de Jong, I.G., Goepfert, A., Glatter, T., Gerdes, K., Schirmer, T., Dehio, C., Adenylylation of gyrase and Topo IV by FicT toxins disrupts bacterial DNA topology. Cell Rep. 12 (2015), 1497–1507.
57. Harms, A., Maisonneuve, E., Gerdes, K., Mechanisms of bacterial persistence during stress and antibiotic exposure. Science 354 (2016), aaf4268-1–aaf4628-9.
58. Harms, A., Fino, C., Sorensen, M.A., Semsey, S., Gerdes, K., Prophages and growth dynamics confound experimental results with antibiotic-tolerant persister cells. MBio, 8, 2017 e01964-17.
59. Harrison, J.J., Wade, W.D., Akierman, S., Vacchi-Suzzi, C., Stremick, C.A., Turner, R.J., Ceri, H., The chromosomal toxin gene yafQ is a determinant of multidrug tolerance for Escherichia coli growing in a biofilm. Antimicrob. Agents Chemother. 53 (2009), 2253–2258.
60. Helaine, S., Cheverton, A.M., Watson, K.G., Faure, L.M., Matthews, S.A., Holden, D.W., Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343 (2014), 204–208.
61. Heller, D.M., Tavag, M., Hochschild, A., CbtA toxin of Escherichia coli inhibits cell division and cell elongation via direct and independent interactions with FtsZ and MreB. PLoS Genet., 13, 2017, e1007007.
62. Jankevicius, G., Ariza, A., Ahel, M., Ahel, I., The toxin-antitoxin system DarTG catalyzes reversible ADP-ribosylation of DNA. Mol. Cell 64 (2016), 1109–1116.
63. Jensen, R.B., Gerdes, K., Programmed cell death in bacteria: proteic plasmid stabilization systems. Mol. Microbiol. 17 (1995), 205–210.
64. Jiang, Y., Pogliano, J., Helinski, D.R., Konieczny, I., ParE toxin encoded by the broad-host-range plasmid RK2 is an inhibitor of Escherichia coli gyrase. Mol. Microbiol. 44 (2002), 971–979.
65. Jørgensen, M.G., Pandey, D.P., Jaskolska, M., Gerdes, K., HicA of Escherichia coli defines a novel family of translation-independent mRNA interferases in bacteria and archaea. J. Bacteriol. 191 (2009), 1191–1199.
66. Jurėnas, D., Chatterjee, S., Konijnenberg, A., Sobott, F., Droogmans, L., Garcia-Pino, A., Van Melderen, L., AtaT blocks translation initiation by N-acetylation of the initiator tRNAfMet. Nat. Chem. Biol. 13 (2017), 640–646.
67. Kamada, K., Hanaoka, F., Burley, S.K., Crystal structure of the MazE/MazF complex: molecular bases of antidote-toxin recognition. Mol. Cell 11 (2003), 875–884.
68. Kawano, M., Aravind, L., Storz, G., An antisense RNA controls synthesis of an SOS-induced toxin evolved from an antitoxin. Mol. Microbiol. 64 (2007), 738–754.
69. Keren, I., Shah, D., Spoering, A., Kaldalu, N., Lewis, K., Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 186 (2004), 8172–8180.
70. Keren, I., Minami, S., Rubin, E., Lewis, K., Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. MBio 2 (2011), e00100–e00111.
71. Koga, M., Otsuka, Y., Lemire, S., Yonesaki, T., Escherichia coli rnlA and rnlB compose a novel toxin-antitoxin system. Genetics 187 (2011), 123–130.
72. Kotte, O., Volkmer, B., Radzikowski, J.L., Heinemann, M., Phenotypic bistability in Escherichia coli's central carbon metabolism. Mol. Syst. Biol., 10, 2014, 736.
73. Lehnherr, H., Maguin, E., Jafri, S., Yarmolinsky, M.B., Plasmid addiction genes of bacteriophage P1: doc, which causes cell death on curing of prophage, and phd, which prevents host death when prophage is retained. J. Mol. Biol. 233 (1993), 414–428.
74. Leplae, R., Geeraerts, D., Hallez, R., Guglielmini, J., Drèze, P., Van Melderen, L., Diversity of bacterial type II toxin-antitoxin systems: a comprehensive search and functional analysis of novel families. Nucleic Acids Res. 39 (2011), 5513–5525.
75. Li, G.W., Burkhardt, D., Gross, C., Weissman, J.S., Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources. Cell 157 (2014), 624–635.
76. Lin, C.Y., Awano, N., Masuda, H., Park, J.H., Inouye, M., Transcriptional repressor HipB regulates the multiple promoters in Escherichia coli. J. Mol. Microbiol. Biotechnol. 23 (2013), 440–447.
77. Lobato-Márquez, D., Moreno-Córdoba, I., Figueroa, V., Díaz-Orejas, R., García-del Portillo, F., Distinct type I and type II toxin-antitoxin modules control Salmonella lifestyle inside eukaryotic cells. Sci. Rep., 5, 2015, 9374.
78. Loris, R., Garcia-Pino, A., Disorder- and dynamics-based regulatory mechanisms in toxin-antitoxin modules. Chem. Rev. 114 (2014), 6933–6947.
79. Lou, C., Li, Z., Ouyang, Q., A molecular model for persister in E. coli. J. Theor. Biol. 255 (2008), 205–209.
80. Magnuson, R.D., Hypothetical functions of toxin-antitoxin systems. J. Bacteriol. 189 (2007), 6089–6092.
81. Maisonneuve, E., Gerdes, K., Molecular mechanisms underlying bacterial persisters. Cell 157 (2014), 539–548.
82. Maisonneuve, E., Shakespeare, L.J., Jørgensen, M.G., Gerdes, K., Bacterial persistence by RNA endonucleases. Proc. Natl. Acad. Sci. USA 108 (2011), 13206–13211.
83. Masuda, H., Inouye, M., Toxins of prokaryotic toxin-antitoxin systems with sequence-specific endoribonuclease activity. Toxins (Basel), 9, 2017, E140.
84. Masuda, H., Tan, Q., Awano, N., Wu, K.P., Inouye, M., YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli. Mol. Microbiol. 84 (2012), 979–989.
85. McVicker, G., Tang, C.M., Deletion of toxin-antitoxin systems in the evolution of Shigella sonnei as a host-adapted pathogen. Nat. Microbiol., 2, 2016, 16204.
86. Monti, M.C., Hernández-Arriaga, A.M., Kamphuis, M.B., López-Villarejo, J., Heck, A.J., Boelens, R., Díaz-Orejas, R., van den Heuvel, R.H., Interactions of Kid-Kis toxin-antitoxin complexes with the parD operator-promoter region of plasmid R1 are piloted by the Kis antitoxin and tuned by the stoichiometry of Kid-Kis oligomers. Nucleic Acids Res. 35 (2007), 1737–1749.
87. Moyed, H.S., Bertrand, K.P., hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 155 (1983), 768–775.
88. Muthuramalingam, M., White, J.C., Bourne, C.R., Toxin-antitoxin modules are pliable switches activated by multiple protease pathways. Toxins (Basel), 8, 2016, E214.
89. Mutschler, H., Gebhardt, M., Shoeman, R.L., Meinhart, A., A novel mechanism of programmed cell death in bacteria by toxin-antitoxin systems corrupts peptidoglycan synthesis. PLoS Biol., 9, 2011, e1001033.
90. Norton, J.P., Mulvey, M.A., Toxin-antitoxin systems are important for niche-specific colonization and stress resistance of uropathogenic Escherichia coli. PLoS Pathog., 8, 2012, e1002954.
91. Ogura, T., Hiraga, S., Mini-F plasmid genes that couple host cell division to plasmid proliferation. Proc. Natl. Acad. Sci. USA 80 (1983), 4784–4788.
92. Otsuka, Y., Yonesaki, T., Dmd of bacteriophage T4 functions as an antitoxin against Escherichia coli LsoA and RnlA toxins. Mol. Microbiol. 83 (2012), 669–681.
93. Overgaard, M., Borch, J., Jørgensen, M.G., Gerdes, K., Messenger RNA interferase RelE controls relBE transcription by conditional cooperativity. Mol. Microbiol. 69 (2008), 841–857.
94. Page, R., Peti, W., Toxin-antitoxin systems in bacterial growth arrest and persistence. Nat. Chem. Biol. 12 (2016), 208–214.
95. Pandey, D.P., Gerdes, K., Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res. 33 (2005), 966–976.
96. Pecota, D.C., Wood, T.K., Exclusion of T4 phage by the hok/sok killer locus from plasmid R1. J. Bacteriol. 178 (1996), 2044–2050.
97. Pedersen, K., Gerdes, K., Multiple hok genes on the chromosome of Escherichia coli. Mol. Microbiol. 32 (1999), 1090–1102.
98. Pedersen, K., Christensen, S.K., Gerdes, K., Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins. Mol. Microbiol. 45 (2002), 501–510.
99. Pedersen, K., Zavialov, A.V., Pavlov, M.Y., Elf, J., Gerdes, K., Ehrenberg, M., The bacterial toxin RelE displays codon-specific cleavage of mRNAs in the ribosomal A site. Cell 112 (2003), 131–140.
100. Pimentel, B., Nair, R., Bermejo-Rodríguez, C., Preston, M.A., Agu, C.A., Wang, X., Bernal, J.A., Sherratt, D.J., de la Cueva-Méndez, G., Toxin Kid uncouples DNA replication and cell division to enforce retention of plasmid R1 in Escherichia coli cells. Proc. Natl. Acad. Sci. USA 111 (2014), 2734–2739.
101. Ramage, H.R., Connolly, L.E., Cox, J.S., Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution. PLoS Genet., 5, 2009, e1000767.
102. Rao, F., Short, F.L., Voss, J.E., Blower, T.R., Orme, A.L., Whittaker, T.E., Luisi, B.F., Salmond, G.P., Co-evolution of quaternary organization and novel RNA tertiary interactions revealed in the crystal structure of a bacterial protein-RNA toxin-antitoxin system. Nucleic Acids Res. 43 (2015), 9529–9540.
103. Raumann, B.E., Rould, M.A., Pabo, C.O., Sauer, R.T., DNA recognition by beta-sheets in the Arc repressor-operator crystal structure. Nature 367 (1994), 754–757.
104. Roberts, R.C., Ström, A.R., Helinski, D.R., The parDE operon of the broad-host-range plasmid RK2 specifies growth inhibition associated with plasmid loss. J. Mol. Biol. 237 (1994), 35–51.
105. Sberro, H., Leavitt, A., Kiro, R., Koh, E., Peleg, Y., Qimron, U., Sorek, R., Discovery of functional toxin/antitoxin systems in bacteria by shotgun cloning. Mol. Cell 50 (2013), 136–148.
106. Schumacher, M.A., Balani, P., Min, J., Chinnam, N.B., Hansen, S., Vulić M., Lewis, K., Brennan, R.G., HipBA-promoter structures reveal the basis of heritable multidrug tolerance. Nature 524 (2015), 59–64.
107. Shah, D., Zhang, Z., Khodursky, A., Kaldalu, N., Kurg, K., Lewis, K., Persisters: a distinct physiological state of E. coli. BMC Microbiol., 6, 2006, 53.
108. Shan, Y., Brown Gandt, A., Rowe, S.E., Deisinger, J.P., Conlon, B.P., Lewis, K., ATP-dependent persister formation in Escherichia coli. MBio, 8, 2017 e02267-16.
109. Short, F.L., Pei, X.Y., Blower, T.R., Ong, S.L., Fineran, P.C., Luisi, B.F., Salmond, G.P., Selectivity and self-assembly in the control of a bacterial toxin by an antitoxic noncoding RNA pseudoknot. Proc. Natl. Acad. Sci. USA 110 (2013), E241–E249.
110. Simanshu, D.K., Yamaguchi, Y., Park, J.H., Inouye, M., Patel, D.J., Structural basis of mRNA recognition and cleavage by toxin MazF and its regulation by antitoxin MazE in Bacillus subtilis. Mol. Cell 52 (2013), 447–458.
111. Soo, V.W., Wood, T.K., Antitoxin MqsA represses curli formation through the master biofilm regulator CsgD. Sci. Rep., 3, 2013, 3186.
112. Szekeres, S., Dauti, M., Wilde, C., Mazel, D., Rowe-Magnus, D.A., Chromosomal toxin-antitoxin loci can diminish large-scale genome reductions in the absence of selection. Mol. Microbiol. 63 (2007), 1588–1605.
113. Takagi, H., Kakuta, Y., Okada, T., Yao, M., Tanaka, I., Kimura, M., Crystal structure of archaeal toxin-antitoxin RelE-RelB complex with implications for toxin activity and antitoxin effects. Nat. Struct. Mol. Biol. 12 (2005), 327–331.
114. Thisted, T., Gerdes, K., Mechanism of post-segregational killing by the hok/sok system of plasmid R1. Sok antisense RNA regulates hok gene expression indirectly through the overlapping mok gene. J. Mol. Biol. 223 (1992), 41–54.
115. Tian, C., Semsey, S., Mitarai, N., Synchronized switching of multiple toxin-antitoxin modules by (p)ppGpp fluctuation. Nucleic Acids Res. 45 (2017), 8180–8189.
116. Tsuchimoto, S., Ohtsubo, H., Ohtsubo, E., Two genes, pemK and pemI, responsible for stable maintenance of resistance plasmid R100. J. Bacteriol. 170 (1988), 1461–1466.
117. Unterholzner, S.J., Poppenberger, B., Rozhon, W., Toxin-antitoxin systems: biology, identification, and application. Mob. Genet. Elements, 3, 2013, e26219.
118. Van Melderen, L., Toxin-antitoxin systems: why so many, what for?. Curr. Opin. Microbiol. 13 (2010), 781–785.
119. Van Melderen, L., Bernard, P., Couturier, M., Lon-dependent proteolysis of CcdA is the key control for activation of CcdB in plasmid-free segregant bacteria. Mol. Microbiol. 11 (1994), 1151–1157.
120. Vandervelde, A., Drobnak, I., Hadži, S., Sterckx, Y.G., Welte, T., De Greve, H., Charlier, D., Efremov, R., Loris, R., Lah, J., Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon. Nucleic Acids Res. 45 (2017), 2937–2950.
121. Veening, J.W., Smits, W.K., Kuipers, O.P., Bistability, epigenetics, and bet-hedging in bacteria. Annu. Rev. Microbiol. 62 (2008), 193–210.
122. Verstraeten, N., Knapen, W.J., Kint, C.I., Liebens, V., Van den Bergh, B., Dewachter, L., Michiels, J.E., Fu, Q., David, C.C., Fierro, A.C., et al. Obg and membrane depolarization are part of a microbial bet-hedging strategy that leads to antibiotic tolerance. Mol. Cell 59 (2015), 9–21.
123. Volante, A., Soberon, N.E., Ayora, S., Alonso, J.C., The interplay between different stability systems contributes to faithful segregation: Streptococcus pyogenes pSM19035 as a model. Microbiol. Spectr., 2, 2014 PLAS-0007-2013.
124. Wang, X., Kim, Y., Hong, S.H., Ma, Q., Brown, B.L., Pu, M., Tarone, A.M., Benedik, M.J., Peti, W., Page, R., Wood, T.K., Antitoxin MqsA helps mediate the bacterial general stress response. Nat. Chem. Biol. 7 (2011), 359–366.
125. Wang, X., Lord, D.M., Cheng, H.Y., Osbourne, D.O., Hong, S.H., Sanchez-Torres, V., Quiroga, C., Zheng, K., Herrmann, T., Peti, W., et al. A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat. Chem. Biol. 8 (2012), 855–861.
126. Wen, J., Fozo, E.M., sRNA antitoxins: more than one way to repress a toxin. Toxins (Basel) 6 (2014), 2310–2335.
127. Wen, Z., Wang, P., Sun, C., Guo, Y., Wang, X., Interaction of type IV toxin/antitoxin systems in cryptic prophages of Escherichia coli K-12. Toxins (Basel), 9, 2017, E77.
128. Wilbaux, M., Mine, N., Guérout, A.M., Mazel, D., Van Melderen, L., Functional interactions between coexisting toxin-antitoxin systems of the ccd family in Escherichia coli O157:H7. J. Bacteriol. 189 (2007), 2712–2719.
129. Winther, K.S., Gerdes, K., Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA. Proc. Natl. Acad. Sci. USA 108 (2011), 7403–7407.
130. Winther, K., Tree, J.J., Tollervey, D., Gerdes, K., VapCs of Mycobacterium tuberculosis cleave RNAs essential for translation. Nucleic Acids Res. 44 (2016), 9860–9871.
131. Wozniak, R.A., Waldor, M.K., A toxin-antitoxin system promotes the maintenance of an integrative conjugative element. PLoS Genet., 5, 2009, e1000439.
132. Wu, N., He, L., Cui, P., Wang, W., Yuan, Y., Liu, S., Xu, T., Zhang, S., Wu, J., Zhang, W., Zhang, Y., 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, 2015, 1003.
133. Zhang, Y., Zhang, J., Hoeflich, K.P., Ikura, M., Qing, G., Inouye, M., MazF cleaves cellular mRNAs specifically at ACA to block protein synthesis in Escherichia coli. Mol. Cell 12 (2003), 913–923.