One cannot rule them all: Are bacterial toxins-antitoxins druggable?

FEMS Microbiology Reviews

Volumn 39, Issue 4, 2015, Pages 522-540

  Chan, Wai Ting ^a   Balsa, Dolors ^b   Espinosa, Manuel ^a  

^a CENTRO DE INVESTIGACIONES BIOLÓGICAS   (Spain)

^b Laboratorios LETI   (Spain)

Author keywords

Antibacterials; Antivirals; Drug delivery; Drug discovery; Inhibitors of protein protein interactions; Persistence; Toxin antitoxin operons

Indexed keywords

ANTIINFECTIVE AGENT; ANTITOXIN; ANTIVIRUS AGENT; BACTERIAL TOXIN;

ANTIBIOTIC RESISTANCE; ANTIBIOTIC THERAPY; APOPTOSIS; BACTERIAL VIRULENCE; BACTERIOSTASIS; BINDING AFFINITY; BIOFILM; CHEMICAL MODIFICATION; DRUG DELIVERY SYSTEM; DRUG FORMULATION; ENVIRONMENTAL CHANGE; EUKARYOTIC CELL; HEPATITIS B; HEPATITIS C; HERPES SIMPLEX; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYDROGEN BOND; INFLUENZA; MOLECULAR DOCKING; MOLECULAR WEIGHT; NONHUMAN; OPERATOR GENE; PROMOTER REGION; PROTEIN PROTEIN INTERACTION; REVIEW; RNA DEGRADATION; TRANSACTIVATION; VACCINATION; ANIMAL; BACTERIAL INFECTIONS; GENETICS; METABOLISM; VIRUS DISEASES;

ANIMALS; ANTI-BACTERIAL AGENTS; ANTITOXINS; ANTIVIRAL AGENTS; BACTERIAL INFECTIONS; BACTERIAL TOXINS; HUMANS; VIRUS DISEASES;

EID: 84940007260     PISSN: 01686445     EISSN: 15746976     Source Type: Journal    
DOI: 10.1093/femsre/fuv002     Document Type: Review

References (173)

1. Agarwal S, Mishra NK, Bhatnagar S, et al. PemK toxin of Bacillus anthracis is a ribonuclease. J Biol Chem 2010;285:7254-70
2. Alonso JC, Balsa D, Cherny I, et al. Bacterial toxin-antitoxin systems as targets for the development of novel antibiotics. In: Bonomo RA, Tolmasky ME, et al. (eds). Enzyme-Mediated antitoxin systems. Structure 2010;18:996-1010
3. Bai H, Luo X. Antisense antibacterials: from proof-of-concept to therapeutic perspectives. In: Bobbarala V (ed). A Search for Antibacterial Agents. InTech, 2012, DOI: 10.5772/33347. Available from: http://www.intechopen.com/books/a-search-forantibacterialagents/antisense-antibacterials-from-proof-ofconcept-to-therapeutic-perspectives
4. Baker M. Fragment-based lead discovery grows up. Nat Rev Drug Discov 2013;12:5-7
5. Bassetti M, Merelli M, Temperoni C, et al. New antibiotics for bad bugs: where are we? Annals Clin Microbiol Antimicrob 2013;12:22-37
6. Bernard P, Gabant P, Bahassi EM, et al. Positive-selection vectors using the F plasmid ccdB killer gene. Gene 1994;148: 71-4
7. Bienstock RJ. Computational drug design targeting protein- protein interactions. Curr Pharm Des 2012;18:1240-54
8. Blair JMA,Webber MA, Baylay AJ, et al. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 2015;13:42-51
9. Bøggild A, Sofos N, Andersen KR, et al. The crystal structure of the intact Escherichia coli RelBE toxin-antitoxin complex provides the structural basis for conditional cooperativity. Structure 2012;20:1641-6
10. Boucher HW, Talbot GH, Benjamin DK, et al. 10× '20 Progress- development of new drugs active against Gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1685-94
11. Bravo A, de Torrontegui G, Diáz R. Identification of components of a new stability system of plasmid R1, Par D, that is close to the origin of replication of this plasmid. Mol Gen Genet 1987;210:101-10
12. Bravo A, Ortega S, de Torrontegui G, et al. Killing of Escherichia coli cells modulated by components of the stability system ParD of plasmid R1. Mol Gen Genet 1988;215:146-51
13. Brown BL, Grigoriu S, Kim Y, et al. 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 2009;5:e1000706.
14. Brown BL, Lord DM, Grigoriu S, et al. The Escherichia coli toxin MqsR destabilizes the transcriptional repression complex formed between the antitoxin MqsA and the mqsRA operon promoter. J Biol Chem 2013;288:1286-94
15. Brown EM, Nathwani D. Antibiotic cycling or rotation: a systematic review of the evidence of efficacy. J Antimicrob Chemoth 2005;55:6-9
16. Camacho AG, Misselwitz R, Behlke J, et al. In vitro and in vivo stability of the epsilon2zeta2 protein complex of the broad hostrange Streptococcus pyogenes pSM19035 addiction system. Biol Chem 2002;383:1701-13
17. Castro-Roa D, Garcia-Pino A, De Gieter S, et al. The Fic protein Doc uses an inverted substrate to phosphorylate and inactivate EF-Tu. Nat Chem Biol 2013;9:811-7
18. Cataudella I, Trusina A, Sneppen K, et al. Conditional cooperativity in toxin-antitoxin regulation prevents random toxin activation and promotes fast translational recovery. Nucleic Acids Res 2012;40:6424-34
19. ChanWT, Moreno-Ćordoba I, Yeo CC, et al. Toxin-antitoxin genes of the gram-positive pathogen Streptococcus pneumoniae: so few and yet so many. Microbiol Mol Biol R 2012;76:773-91
20. Chan WT, Moreno-Ćordoba I, Yeo CC, et al. Toxin-antitoxin loci in Streptococcus pneumoniae. In: Gerdes K, et al. (ed). Prokaryotic Toxin-Antitoxins. Berlin, Heidelberg: Springer-Verlag, 2013, 315-339
21. Chan WT, Yeo CC, Sadowy E, et al. Functional validation of putative toxin-antitoxin genes from the Gram-positive pathogen Streptococcus pneumoniae: phd-doc is the fourth bona-fide operon. Front Microbiol 2014;5:677.
22. Chono H, Matsumoto K, Tsuda H, et al. Acquisition of HIV-1 resistance in T lymphocytes using an ACA-specific Escherichia coli mRNA interferase. Hum Gene Ther 2011a;22:35-43
23. Chono H, Saito N, Tsuda H, et al. In vivo safety and persistence of endoribonuclease gene-transduced CD4+ T cells in cynomolgus macaques for HIV-1 gene therapy model. PLoS One 2011b;6:e23585.
24. Christensen KS, Maenhauf-Michel G, Mine N, et al. Overproduction of the Lon protease triggers inhibition of translation in Escherichia coli: involvement of the yefM-yoeB toxin-antitoxin system. Mol Microbiol 2004;51:1705-17
25. Christensen SK, Mikkelsen M, Pedersen K, et al. RelE, a global inhibitor of translation, is activated during nutritional stress. P Natl Acad Sci USA 2001;98:14328-33
26. Congreve M, Carr R, Murray C, et al. A 'Rule of Three' for fragment-based lead discovery? Drug Discov Today 2003;8:876-7
27. Conlon BP, Nakayasu ES, Fleck LE, et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 2013;503:365-70
28. Dao-Thi MH, Van Melderen L, DeGenst E, et al. Molecular basis of gyrase poisoning by the addiction toxin CcdB. J Mol Biol 2005;348:1091-102
29. Davies J, Davies D Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010;74:417-33
30. Davis TL, Helinski DR, Roberts RC. Transcription and autoregulation of the stabilizing functions of broad-host-range plasmid RK2 in Escherichia coli, Agrobacterium tumefaciens and Pseudomonas aeruginosa. Mol Microbiol 1992;6:1981-94.
31. de Bast MS, Mine N, van Melderen L. Chromosomal toxinantitoxin systems may act as antiaddiction modules. J Bacteriol 2008;190:4603-9
32. DeClercq E. In search of a selective therapy of viral infections. Antivir Res 2010;85:19-24
33. De la Cruz MA, Zhao W, Farenc C, et al. A toxin-antitoxin module of Salmonella promotes virulence in mice. PLoS Pathog 2013;9:e1003827.
34. de la Cueva-Méndez G. Systems and methods for diminishing cell growth and including selective killing of target cells. Medical Research Council UK EP 2570134 A1. 2013.
35. de la Cueva Méndez G, Mills AD, Clay Farrace L, et al. Regulatable killing of eukaryotic cells by the prokaryotic proteins Kid and Kis. EMBO J 2003;22:246-51
36. Deresinski S. Bacteriophage therapy: exploiting smaller fleas. Clin Infect Dis 2009;48:1096-101
37. Dienemann C, Bøggild A, Winther KS, et al. Crystal structure of the VapBC toxin-antitoxin complex from Shigella flexneri reveals a hetero-octameric DNA-binding assembly. J Mol Biol 2011;414:713-22
38. Engelberg-Kulka H, Glaser G. Addiction modules and programmed cell death and antideath in bacterial cultures. Annu Rev Microbiol 1999;53:43-70
39. Erlanson DA, McDowell RS, O'Brien T. Fragment-based drug discovery. J Med Chem 2004;47:3463-82
40. Espinosa M, Lopez P, Lacks SA. Transfer and expression of recombinant plasmids carrying pneumococcal mal genes in Bacillus subtilis. Gene 1984;28:301-10
41. Falagas ME, Karageorgopoulos DE. Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology. Clin Infect Dis 2008;46:1121-2
42. Faridani OR, Nikravesh A, Pandey DP, et al. Competitive inhibition of natural antisense Sok-RNA interactions activates Hok-mediated cell killing in Escherichia coli. Nucleic Acids Res 2006;34:5915-22
43. Fasani RA, Savageau MA. Molecular mechanisms of multiple toxin-antitoxin systems are coordinated to govern the persister phenotype. P Natl Acad Sci USA 2013;110:E2528-37
44. Feng S, Chen Y, Kamada K, et al. YoeB-ribosome structure: a canonical RNase that requires the ribosome for its specific activity. Nucleic Acids Res 2013;41:9549-56
45. Fernandez-Lopez R, Machon C, Longshaw CM, et al. Unsaturated fatty acids are inhibitors of bacterial conjugation. Microbiology 2005;151:3517-26
46. Francuski D, SaengerW. Crystal structure of the antitoxin-toxin protein complex RelB-RelE from Methanococcus jannaschii. J Mol Biol 2009;393:898-908
47. Gazit E, Sauer RT. Stability and DNA binding of the Phd protein of the phage P1 plasmid addiction system. J Biol Chem 1999;274:2652-7
48. Geller BL, Marshall-Batty K, Schnell FJ, et al. Gene-silencing antisense oligomers inhibit Acinetobacter growth in vitro and in vivo. J Infect Dis 2013;208:1553-60
49. Georgiades K. Genomics of epidemic pathogens. Clin Microbiol Infect 2012;18:213-7
50. Georgiades K, Raoult D. Genomes of the most dangerous epidemic bacteria have a virulence repertoire characterized by fewer genes but more toxin-antitoxin modules. PLoS One 2011;6:e17962.
51. Gerdes K. Prokaryotic Toxin-Antitoxins. Berlin-Heidelberg: Springer, 2013.
52. Gerdes K, Christensen KS, Lobner-Olensen A. Prokaryotic toxinantitoxin stress response loci Nat Rev Microbiol 2005;3:371-82
53. Gerdes K, Maisonneuve E. Bacterial persistence and toxinantitoxin loci. Annu Rev Microbiol 2012;66:103-23
54. Germain E, Castro-Roa D, Zenkin N, et al. Molecular mechanism of bacterial persistence by HipA. Mol Cell 2013;52:248-54
55. Grady R, Hayes F. Axe-Txe, a broad-spectrum proteic toxinantitoxin system by a multidrug-resistant, clinical isolate of Enterococcus faecium. Mol Microbiol 2003;47:1419-32
56. Guan L, Liu Q, Li CX, et al. Development of a Fur-dependent and tightly regulated expression system in Escherichia coli for toxic protein synthesis. BMC Biotechnol 2013;13:25.
57. Hansen S, Vulíc M, Min J, et al. Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis. PLoS ONE 2012;7:e39185.
58. Hargreaves D, Santos-Sierra S, Giraldo R, et al. Structural and functional analysis of the Kid toxin protein from Escherichia coli plasmid R1. Structure 2002;10:1425-33
59. Harrison JJ,Wade WD, Akierman S, et al. The chromosomal toxin yafQ is a determinant of multidrug tolerance for Escherichia coli growing in a biofilm. Antimicrob Agents Ch 2009;53: 2253-8
60. Hayes F.Moving in for the kill: activation of an endoribonuclease toxin by a quorum-sensing peptide. Mol Cell 2011;41:617-8
61. Hayes F, Van Melderen L. Toxins-antitoxins: diversity, evolution and function. Crit Rev Biochem Mol 2011;46:386-408
62. Head MG, Fitchett JR, Cooke MK, et al. Systematic analysis of funding awarded for antimicrobial resistance research to institutions in the UK, 1997-2010 J Antimicrob Chemoth 2014;69:548-54
63. Heaton BE, Herrou J, Blackwell AE, et al. Molecular structure and function of the novel BrnT/BrnA toxin-antitoxin system of Brucella abortus. J Biol Chem 2012;287:12098- 110.
64. Huang S-Y. Search strategies and evaluation in protein-protein docking: principles, advances and challenges. Drug Discov Today 2014;19:1081-96
65. Hurley JM, Woychik NA. Bacterial toxin HigB associates with ribosomes and mediates translation-dependent mRNA cleavage at A-rich sites. J Biol Chem 2009;284:18605-13
66. Huys I, Pirnay JP, Lavigne R, et al. Paving a regulatory pathway for phage therapy. EMBO Rep 2013;14:951-4
67. Imamovic L, SommerMOA. Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. Sci Transl Med 2013;5:204ra132.
68. Inouye M. The discovery of mRNA interferases: implication in bacterial physiology and application to biotechnology. J Cell Physiol 2006;209:670-6
69. Ji Y, Marra A, Rosenberg M, et al. Regulated antisense RNA eliminates alpha-toxin virulence in Staphylococcus aureus infection. J Bacteriol 1999;181:6585-90
70. Jiang Y, Pogliano J, Helinski DR, et al. ParE toxin encoded by the broad-host-range plasmid RK2 is an inhibitor of Escherichia coli gyrase. Mol Microbiol 2002;44:971-9
71. Jørgensen MG, Pandey DP, Jaskolska M, et al. HicA of Escherichia coli defines a novel family of translation-independent mRNA interferases in bacteria and archaea. J Bacteriol 2009;191:1191-9
72. Kamada K, Hanaoka F, Burley SK. Crystal structure of the MazE/MazF complex: molecular bases of antidote-toxin recognition. Mol Cell 2003;11:875-84
73. Kamphuis MB, Monti MC, van den Heuvel RHH, et al. Structure and function of bacterial Kid-Kis and related toxin-antitoxin systems. Protein Peptide Lett 2007;14:113-24
74. Kaplan SL, Mason EO, Jr. Management of infections due to antibiotic-resistant Streptococcus pneumoniae. Clin Microbiol Rev 1998;11:628-44
75. Kawano M, Aravind L, Storz G. An antisense RNA controls synthesis of an SOS-induced toxin evolved from an antitoxin. Mol Microbiol 2007;64:738-54
76. Kim Y,Wang X, Ma Q, et al. Toxin-antitoxin systems in Escherichia coli influence biofilm formation through YjgK (TabA) and fimbriae. J Bacteriol 2009;191:1258-67
77. Kinch MS, Patridge E, Plummer M, et al. An analysis of FDAapproved drugs for infectious disease: antibacterial agents Drug Discov Today 2014;19:1283-7
78. Kolodkin-Gal I, Verdiger R, Shlosberg-Fedida A, et al. A differential effect of Escherichia coli toxin-antitoxin systems on cell death in liquid media and biofilm formation. PLoS One 2009;4:e6785.
79. Korch SB, Hill TM. Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation. J Bacteriol 2006;188:3826- 36.
80. Kumar P, Issac B, Dodson EJ, et al. Crystal structure of Mycobacterium tuberculosis YefM antitoxin reveals that it is not Acids Res 2011;39:5513-25
81. Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol 2007;5:48-56
82. Lewis K. Multidrug tolerance of biofilms and persister cells Curr Top Microbiol Immunol 2008;322:107-31
83. Lewis K. Persister cells. Annu Rev Microbiol 2010;64:357-72
84. Lioy VS, Rey O, Balsa D, et al. A toxin-antitoxin module as a target for antimicrobial development. Plasmid 2010;63:31-9
85. Littler E, Oberg B. Achievements and challenges in antiviral drug discovery. Antivir Chem Chemoth 2005;16:155-68
86. Ĺopez-Villarejo J, Diago-Navarro E, Hernández-Arriaga AM, et al. Kis antitoxin couples plasmid R1 replication and parD (kis, kid) maintenance modules. Plasmid 2012;67:118-27
87. Loris R, Dao Thi M-H, Bahassi L, et al. Crystal structure of CcdB, a topoisomerase poison from E. coli. J Mol Biol 1999;285:1667- 77.
88. MacDiarmid JA, Mugridge NB, Weiss JC, et al. Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics. Cancer Cell 2007;11:431-45
89. McKenzie JL, Robson J, Berney M, et al. A VapBC toxinantitoxin module is a post-transcriptional regulator of metabolic flux in mycobacteria. J Bacteriol 2012;194:2189- 204.
90. Maisonneuve E, Castro-Camargo M, Gerdes K. (p)ppGpp controls bacterial persistence by stochastic induction of toxinantitoxin activity. Cell 2013;154:1140-50
91. Maisonneuve E, Shakespeare LJ, Jørgensen MG, et al. Bacterial persistence by RNA endonucleases. P Natl Acad Sci USA 2011;108:13206-11
92. Makarova KS, Grishin NV, Koonin EV. The HicAB cassette, a putative novel, RNA-targeting toxin-antitoxin system in archaea and bacteria. Bioinformatics 2006;22:2581-4
93. Makarova KS, Wolf YI, Snir S, et al. Defense islands in bacterial and archaeal genomes and prediction of novel defense systems. J Bacteriol 2011;193:6039-56
94. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72
95. Marra A. Can virulence factors be viable antibacterial targets? Expert Rev Anti-Infe 2004;2:61-72
96. Masuda H, Tan Q, Awano N, et al. YeeU enhances the bundling of cytoskeltal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli. Mol Microbiol 2012;84:979-89
97. Miallau L, Faller M, Chiang J, et al. Structure and proposed activity of a member of the VapBC family of toxin-antitoxin systems. VapBC-5 from Mycobacterium tuberculosis. J Biol Chem 2009;284:276-83
98. Mitchell HL, Dashper SG, Catmull DV, et al. Treponema denticola biofilm-induced expression of a bacteriophage, toxin-antitoxin systems and transposases. Microbiology 2009;156:774-88
99. Monti MC, Hernandez-Arriaga AM, Kamphuis MB, et al. 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 2007;35:1737-49
100. Moyed HS, Bertrand KP. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 1983;155: 768-75
101. Mruk I, Kobayashi I. To be or not to be: regulation of restriction- modification systems and other toxin-antitoxin systems. Nucleic Acids Res 2014;42:70-86
102. Mutschler H, Gebhardt M, Shoeman RL, et al. A novel mechanism of programmed cell death in bacteria by toxinantitoxin systems corrupts peptidoglycan synthesis. PLoS Biol 2011;9:e1001033.
103. Mutschler H, Meinhart A. systems: their role in resistance, virulence, and their potential for antibiotic development. J Mol Med 2011;89:1183-94
104. Mutschler H, Reinstein J, Meinhart A. Assembly dynamics and stability of the pneumococcal Epsilon Zeta antitoxin toxin (PezAT) system from Streptococcus pneumoniae. J Biol Chem 2010;285:21797-806
105. Nariya H, Inouye M. MazF, an mRNA interferase, mediates programmed cell death during multicellular Myxococcus development. Cell 2008;132:55-66
106. Nielsen PE, Egholm M. An introduction to peptide nucleic acid. Curr Issues Mol Biol 1999;1:89-104
107. Nieto C, Pellicer T, Balsa D, et al. The chromosomal relBE2 toxin-antitoxin locus of Streptococcus pneumoniae: characterization and use of a bioluminescence resonance energy transfer assay to detect toxin-antitoxin interaction. Mol Microbiol 2006;59:1280-96
108. Nieto C, Sadowy E, de la Campa AG, et al. The relBE2Spn toxinantitoxin system of Streptococcus pneumoniae: role in antibiotic tolerance and functional conservation in clinical isolates. PLoS One 2010;5:e11289.
109. Norton JP, Mulvey MA. Toxin-antitoxin systems are important for niche-specific colonization and stress resistance of uropathogenic Escherichia coli. PLoS Pathog 2012;8:e1002954.
110. Oberer M, Zangger K, Gruber K, et al. The solution structure of ParD, the antidote of the ParDE toxin antitoxin module, provides the structural basis for DNA and toxin binding. Protein Sci 2007;16:1676-88
111. Oberer M, Zangger K, Prytulla S, et al. The anti-toxin ParD of plasmid RK2 consists of two structurally distinct moieties and belongs to the ribbon-helix-helix family of DNA binding proteins. Biochem J 2002;361:41-7
112. Overgaard M, Borch J, Gerdes K. RelB and RelE of Escherichia coli form a tight complex that represses transcription via the ribbon-helix-helix motif in RelB. J Mol Biol 2009;394: 183-96
113. Pandey DP, Gerdes K. Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res 2005;33:966-76
114. Park J-H, Yamaguchi Y, Inouye M. Intramolecular regulation of the sequence-specific mRNA interferase activity of MazF fused to a MazE fragment with a linker cleavable by specific proteases. Appl Environ Microb 2012;78:3794-9
115. Park S, Mann J, Li N. Targeted inhibitor design: lessons from small molecule drug design, directed evolution, and vaccine research. Chem Eng Process Tech 2013;1:1004.
116. Park SJ, Son WS, Lee B-J. Structural overview of toxin-antitoxin systems in infectious bacteria: A target for developing antimicrobial agents. Biochim Biophys Acta-Proteins and Proteomics 2013;1834:1155-67
117. Pecota DC, Kim CS,Wu K, et al. Combining the hok/sok, parDE, and pnd, postsegregational killer loci to enhance plasmid stability. Appl Environ Microb 1997;63:1917-24
118. Pedersen K, Christensen KS, Gerdes K. Rapid induction and reversal of a bacteriostatic conditions by controlled expression of toxins and antitoxins. Mol Microbiol 2002;45:501-10
119. Pimentel B, Madine MA, de la Cueva-Mendez G. Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1. EMBO J 2005;24:3459-69
120. Ramage HR, Connolly LE, Cox JS. Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution. PLoS Genet 2009;5:e1000767.
121. Ramos JL, Diáz E, Dowling D, et al. The behavior of bacteria designed for biodegradation. Biotechnology 1994;12:1349-56
122. Ray A, Nordén B. Peptide nucleic acid (PNA): its medical and biotechnical applications and promise for the future. FASEB J 2000;14:1041-60
123. Rebuffat S. Microcins in action: amazing defence strategies of Enterobacteria. Biochem Soc T 2012;40:1456-62
124. Ren D, Bedzyk LA, Thomas SM, et al. Gene expression in Escherichia coli biofilms. Appl Microbiol Biot 2004;64:515-24
125. Ren D, Walker A, Daines DA. Toxin-antitoxin loci vapBC-1 and vapXD contribute to survival and virulence in nontypeable Haemophilus influenzae. BMC Microbiol 2012;12:263.
126. Robson J, McKenzie JL, Cursons R, et al. The vapBC Operon from Mycobacterium smegmatis is an autoregulated toxin-antitoxin module that controls growth via inhibition of translation J Mol Biol 2009;390:353-67
127. Rojas-Chapana J, Troszczynska J, Firkowska I, et al. Multi-walled carbon nanotubes for plasmid delivery into Escherichia coli cells. Lab Chip 2005;5:536-9
128. Rowe-Magnus DA, Guerout AM, Biskri L, et al. Comparative analysis of superintegrons: engineering extensive genetic diversity in the Vibrionaceae. Genome Res 2003;13:428-42
129. Samson JE, Magadán AH, Sabri M, et al. Revenge of the phages: defeating bacterial defences. Nat Rev Microbiol 2013;11:675- 87.
130. Samson JE, Spinelli S, Cambillau C, et al. Structure and activity of AbiQ, a lactococcal endoribonuclease belonging to the type III toxin-antitoxin system. Mol Microbiol 2013;87:756-68
131. Saxena SK, Mishra N, Saxena R. Advances in antiviral drug discovery and development. Future Virol 2009;4:101-7
132. Sberro H, Leavitt A, Kiro R, et al. Discovery of functional toxin/antitoxin systems in bacteria by shotgun cloning. Mol Cell 2013;50:136-48
133. Schifano JM, Edifor R, Sharp JD, et al. Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site. P Natl Acad Sci USA 2013;110: 8501-6
134. Schumacher MA, Piro KM, Xu W, et al. Molecular mechanisms of HipA-mediatedmultidrug tolerance and its neutralization by HipB. Science 2009;323:396-401
135. Schureck MA,Maehigashi T, Miles SJ, et al. Structure of the P. vulgaris HigB-(HigA)2-HigB toxin-antitoxin complex. J Biol Chem 2014;289:1060-70
136. Sebbage V. Cell-penetrating peptides and their therapeutic applications. Bioscience Horizons 2009;2:64-72
137. Shapira A, Shapira S, Gal-Tanamy M, et al. Removal of hepatitis C virus-infected cells by a zymogenized bacterial toxin. PLoS One 2012;7:e32320.
138. Shimazu T, Mirochnitchenko O, Phadtare S, et al. Regression of solid tumors by induction of MazF, a bacterial mRNA endoribonuclease. J Mol Microb Biotech 2014;24:228-33
139. Shlaes DM, Sahm D, Opiela C, et al. The FDA reboot of antibiotic development. Antimicrob Agents Ch 2013;57:4605-7
140. Soo VW, Wood TK. Antitoxin MqsA represses curli formation through the master biofilm regulator CsgD. Sci Rep 2013;3:3186.
141. Stieber D, Gabant P, Szpirer CY. The art of selective killing: plasmid toxin/antitoxin systems and their technological applications. Biotechniques 2008;45:344-6
142. Suzuki M, Zhang J, Liu M, et al. Single protein production in living cells facilitated by anmRNA interferase. Mol Cell 2005;18:253- 61.
143. Szekeres S, DautiM,Wilde C, et al. Chromosomal toxin-antitoxin loci can diminish large-scale genome reductions in the absence of selection. Mol Microbiol 2007;63:1588-605
144. Takagi H, Kakuta Y, Okada T, et al. Crystal structure of archaeal toxin-antitoxin RelE-RelB complex with implications for toxin activity and antitoxin effects. Nat Struct Mol Biol 2005;12:327-31
145. Torres B, Jaenecke S, Timmis KN, et al. A dual lethal system to enhance containment of recombinant micro-organisms. Microbiology 2003;149:3595-601
146. Trauner A, Sassetti CM, Rubin EJ. Genetic strategies for identifying new drug targets. Microbiol Spectrum 2014;2:MGM2-0030- 2013.
147. Tripathi A, Dewan PC, Barua B, et al. Additional role for the ccd operon of F-plasmid as a transmissible persistence factor. P Natl Acad Sci USA 2012;109:12497-502
148. Unterholzner SJ, Poppenberger B, Rozhon W. Toxin-antitoxin systems: biology, identification, and application. Mob Genet Elements 2013;3:e26219.
149. van Melderen L. Molecular interactions of the CcdB poison with its bacterial target, the DNA gyrase. Int J Med Microbiol 2002;291:537-44.
150. van Melderen L. Toxin-antitoxin systems: why so many, what for? Curr Opin Microbiol 2010;13:781-5
151. VanMelderen L, Dao Thi M-H, Lecchi P, et al. ATP-dependent degradation of CcdA by Lon protease. Effects of secondary structure and heterologous subunit interactions. J Biol Chem 1996;271:27730-8.
152. van Melderen L, Saavedra De Bast M. Bacterial toxin- antitoxin systems: more than selfish entities? PLoS Genet 2009;5:e1000437.
153. Wang X, Lord DM, Cheng H-Y, et al. A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat Chem Biol 2012;8:856-61
154. Walsh CT, Fischer SL, Park I-S, et al. Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story. Current Biology 1996;3:21-28
155. Wellington EM, Boxall AB, Cross P, et al. The role of the natural environment in the emergence of antibiotic resistance in Gram-negative bacteria. Lancet Infect Dis 2013;13:155-65
156. Wen Y, Behiels E, Devreese B. Toxin-Antitoxin systems: their role in persistence, biofilm formation and pathogenicity. Pathog Dis 2014;70:240-9
157. Wieteska ±L, Skulimowski A, Cybula M, et al. Toxins VapC and PasB from prokaryotic TA modules remain active in mammalian cancer cells. Toxins 2014;6:2948-61
158. Williams JJ, Hergenrother PJ. Artificial activation of toxinantitoxin systems as an antibacterial strategy. Trends Microbiol 2012;20:291-8
159. Winther KS, Gerdes K. Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA. P Natl Acad Sci USA 2011;108:7403-7
160. Wong BS, Yoong SL, Jagusiak A, et al. Carbon nanotubes for delivery of small molecule drugs. Adv Drug Deliver Rev 2013;65:1964-2015
161. Wozniak RAF, Waldor MK. A toxin-antitoxin system promotes the maintenance of an integrative conjugative element. PLoS Genet 2009;5:e1000439.
162. Wright O, Delmans M, Stan GB, et al. GeneGuard: a modular plasmid system designed for biosafety. ACS Synth Biol 2014. DOI:10.1021/sb500234s.
163. Xu Y, Piston DW, Johnson CH. A bioluminescence resonance energy transfer (BRET) system: application to interaction circadian clock proteins. P Natl Acad Sci USA 1999;96: 151-6
164. Yamaguchi Y, Park J-H, Inouye M. MqsR, a crucial regulator for quorum sensing and biofilm formation, is a GCUspecific mRNA interferase in Escherichia coli. J Biol Chem 2009;284:28746-53
165. Yang L, Cao Z, L iF, et al. Tumor-specific gene expression using the survivin promoter is further increased by hypoxia. Gene Ther 2004;11:1215-23
166. Zhang D, Iyer LM, Burroughs AM, et al. Resilience of biochemical activity in protein domains in the face of structural divergence. Curr Opin Struc Biol 2014;26:92-103
167. Zhang Y, Inouye M. The inhibitory mechanism of protein synthesis by YoeB, an Escherichia coli toxin. J Biol Chem 2009;284:6627-38
168. Zhang Y, Yamaguchi Y, Inouye M. Characterization of YafO, an Escherichia coli toxin. J Biol Chem 2009;284:25522-31
169. Zhang Y, Zhang J, Hoeflich KP, et al. MazF cleaves cellularmRNAs specifically at ACA to block protein synthesis in Escherichia coli. Mol Cell 2003;12:913-23
170. Zhu L, Inoue K, Yoshizumi S, et al.Staphylococcus aureus MazF specifically cleaves a pentad sequence, UACAU, which is unusually abundant in the mRNA for pathogenic adhesive factor SraP. J Bacteriol 2009;191:3248-55
171. Zhu L, Sharp JD, Kobayashi H, et al. Noncognate Mycobacterium tuberculosis toxin-antitoxins can physically and functionally interact. J Biol Chem 2010;285:39732-8
172. Zielenkiewicz U, Ceglowski P. The toxin-antitoxin system of the streptococcal plasmid pSM19035. J Bacteriol 2005;187:6094- 105.
173. Zorko M, Langel U. Cell-penetrating peptides: mechanism and kinetics of cargo delivery. Adv Drug Deliver Rev 2005;57: 529-45.