Bacterial Toxin-Antitoxin Systems and New Strategies for Creating Antibacterial Preparations
Abstract
Intensive research of bacterial toxin-antitoxin systems (TAS) in recent decades has significantly expanded and deepened knowldge about them. As TAS modules were first discovered in the plasmids and later in the chromosomes of bacteria, and after subsequent study of their specific regulation of activation and functions, their image has changed from simple curious genetic objects to one of the most important tools. They play a decisive role in bacterial protection and adaptation to unfavorable growth conditions, including microbial persistence and chronic infection processes, formation of antibiotic resistance. It became clear that these small genetic modules, which can be found almost everywhere in the bacterial genomes, have a high potential for biotechnological and biomedical innovation research, as well as the prospect of developing fundamentally new antibacterial technologies. Given the leading role of TAS for the survival of pathogenic bacteria and the development of the infectious process, modern technologies for creating alternative antibacterial strategies consider these systems to be promising targets for the development of new antimicrobial agents.
About the Authors
B. G. Andryukov
G.P. Somov Research Institute of Epidemiology and Microbiology; Far Eastern Federal University
Russian Federation
Russian Federation
N. N. Besednova
G.P. Somov Research Institute of Epidemiology and Microbiology
Russian Federation
Russian Federation
T. S. Zaporozhets
G.P. Somov Research Institute of Epidemiology and Microbiology
Russian Federation
Russian Federation
M. P. Bynina
G.P. Somov Research Institute of Epidemiology and Microbiology
Russian Federation
Russian Federation
References
1. Kedzierska B., Hayes F. Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis. Molecules 2016; 21. Doi: 10.3390/molecules21060790.
2. Van Melderen L., Saavedra de Bast M. Bacterial toxin-antitoxin systems: More than selfish entities? PLoS Genet 2009; 5: 3: e1000437. Doi: 10.1371/journal.pgen.1000437.
3. Ki-Young Lee., Bong-Jin Lee. Structure, Biology, and Therapeutic Application of Toxin-Antitoxin Systems in Pathogenic Bacteria. Toxins 2016; 8: 10: 305. Doi:10.3390/toxins8100305.
4. Goeders N., Chai R., Chen B., Day A. Salmond G. Structure, Evolution, and Functions of Bacterial Type III Toxin-Antitoxin Systems. Toxins 2016; 8: 10: 282. Doi:10.3390/toxins8100282.
5. Aizenman E., Engelberg-Kulka H., Glaser G. An Escherichia coli chromosomal «addiction module» regulated by guanosine 30,50-bispyrophosphate: a model for programmed bacterial cell death. Proc Natl Acad Sci USA 1996; 93: 6059-6063.
6. Ogura T., Hiraga S. Mini-F plasmid genes that couple host cell division to plasmid proliferation. Proc Natl Acad Sci USA 1983; 80: 4784-4788.
7. 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 1994; 11: 1151-1157.
8. Hayes F. Toxins-antitoxins: Plasmid maintenance, programmed cell death, and cell cycle arrest. Science 2003; 301: 1496-1499. Doi: 10.1126/science.1088157.
9. Yarmolinsky M. B. Programmed cell death in bacterial populations. Science 1995; 267: 836-837.
10. Engelberg-Kulka H., Glaser G. Addiction modules and programmed cell death and antideath in bacterial cultures. Annu. Microbiol Rev 1999; 53: 43-70. Doi: 10.1146/annurev.micro.53.1.43.
11. Engelberg-Kulka H., Amitai S., Kolodkin-Gal I., Hazan R. Bacterial programmed cell death and multicellular behavior in bacteria. PLoS Genet 2006; 2: е135. Doi: 10.1371/journal.pgen.0020135.
12. Erental A., Idith Sh. I., Engelberg-Kulka H. Two Programmed Cell Death Systems in Escherichia coli: An Apoptotic-Like Death Is Inhibited by the mazEF-Mediated Death Pathway. PLoS biology 2012; 3: 10: e100128.
13. Coussens N. P., Daines D. A. Wake me when it’s over-Bacterial toxinantitoxin proteins and induced dormancy. Exp Biol Med 2016; 241: 1332-1342. Doi: 10.1177/1535370216651938.
14. Muthuramalingam M., White J. C., Bourne C. R. Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways. Toxins 2016; 8: 7: 214. Doi:10.3390/toxins8070214.
15. Makarova K. S., Wolf Y. I., Koonin E.V. Comprehensive comparative-genomic analysis of type 2 toxin-antitoxin systems and related mobile stress response systems in prokaryotes. Biol Direct 2009; 4: 11-19.
16. Makarova K. S., Wolf Y. I., Koonin E. V. Comparative genomics of defense systems in archaea and bacteria. Nucleic Acids Res 2013; 41: 4360-4377. Doi: 10.1093/nar/gkt157.
17. Page R., Peti W. Toxin-antitoxin systems in bacterial growth arrest and persistence. Nat Chem Biol 2016; 12: 208-214.
18. Allison K. R., Brynildsen M. P., Collins J. J. Heterogeneous bacterial persisters and engineering approaches to eliminate them. Curr Opin Microbiol 2011; 14: 593-598. Doi: 10.1016/j.mib.2011.09.002.
19. Pimentel B., Nair R., Bermejo-Rodriguez C., Preston M. A., Agu C. A., Wang X., Bernal J. A., Sherratt D. J., de la Cueva-Mendez G. Toxin Kid uncouples DNA replication and cell division to enforce retention of plasmid R1 in Escherichia coli cells. Proc Natl Acad Sci USA 2014; 111: 2734-2739. Doi: 10.1073/pnas.1308241111.
20. Moritz E. M., Hergenrother P. J. Toxin-antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci. Proc Natl Acad Sci USA 2007; 104: 1: 311-316. Doi: 10.1073/pnas.0601168104.
21. Holden D.W. Microbiology. Persisters unmasked. Science 2015; 347: 30-32.
22. Maisonneuve E., Castro-Camargo M., Gerdes K. (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity. Cell 2013; 154: 1140-1150.
23. Gerdes K., Maisonneuv, E. Remarkable functional convergence: Alarmone ppGpp mediates persistence by activating type I and II toxinantitoxins. Mol Cell 2015; 59: 1-3.
24. Meredith H. R., Srimani J. K., Lee A. J., Lopatkin A. J., You L. Collective antibiotic tolerance: Mechanisms, dynamics and intervention. Nat Chem Biol 2015; 11: 182-188. Doi: 10.1038/nchembio.1754.
25. Fasani R. A., Savageau M. A. Unrelated toxin-antitoxin systems cooperate to induce persistence. J R Soc Interface 2015; 12. Doi: 10.1098/rsif.2015.0130.
26. Bigger J. W. Treatment of staphylococcal infections with penicillin by intermittent sterilization. Lancet 1944; 294: 497-500.
27. Levin B. R., Rozen D. E. Non-inherited antibiotic resistance. Nat Rev Microbiol 2006; 4: 556-562.
28. Shan Y., Lazinski D., Rowe S., Camilli A., Lewis K. Genetic basis of persister tolerance to aminoglycosides in Escherichia coli. mBio 2015; 6. Doi: 10.1128/mBio.00078-15.
29. Harms A., Maisonneuve E., Gerdes K. Mechanisms of bacterial persistence during stress and antibiotic exposure. Science 2016; 354: 6318: pii: aaf4268. Doi: http://dx.doi.org/10.1101/200477.
30. Dhar N, McKinney J. D. Microbial phenotypic heterogeneity and antibiotic tolerance. Curr Opin Microbiol 2007; 10: 30-38. Doi: 10.1016/j.copbio.2017.12.007.
31. Liu S., Wu N., Zhang S., Yuan Y., Zhang W., Zhang Y. Variable Persister Gene Interactions with (p)ppGpp for Persister Formation in Escherichia coli. Front Microbiol 2017; 8: 1795. Doi: 10.3389/fmicb.2017.01795.
32. Marques C. N., Morozov A., Planzos P., Zelaya H. M. The fatty acid signaling molecule cis-2-decenoic acid increases metabolic activity and reverts persister cells to an antimicrobial-susceptible state. Appl Environ Microbiol 2014; 80: 6976-6991.
33. Spoering A. L., Lewis K. Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. J Bacteriol 2001; 183: 23: 6746-6751.
34. Wood T.K. Combatting bacterial persister cells. Biotechnol Bioeng 2016; 113: 476-483. Doi: 10,1002 / bit.25721.
35. Fisher R. A., Gollan B., Helaine S. Persistent bacterial infections and per-sister cells. Nat Rev Microbiol 2017; 15: 8: 453-464. Doi: 10.1038/nrmi-cro.2017.42.
36. Garland M., Loscher S., Bogyo M. Chemical Strategies To Target Bacterial Virulence. Chem Rev 2017; 117: 5: 4422-4461. Doi: 10.1021/acs.chemrev.6b00676.
37. Marsan D., Place A., Fucich D., Chen F. Toxin-Antitoxin Systems in Estuarine Synechococcus Strain CB0101 and Their Transcriptomic Responses to Environmental Stressors. Front Microbiol 2017; 8: 1213. Doi: 10.3389/fmicb.2017.01213.
38. Tian C., Semsey S., Mitarai N. Synchronized switching of multiple toxin-antitoxin modules by (p)ppGpp fluctuation. Nucleic Acids Res 2017; 45: 14: 8180-8189. Doi: 10.1093/nar/gkx552.
39. Harms A., Fino C., Srnrensen M. A., Semsey S., Gerdes K. Prophages and Growth Dynamics Confound Experimental Results with AntibioticTolerant Persister Cells. MBio 2017; 8: 6: pii: e01964-17. Doi: 10.1128/mBio.01964-17.
40. Fineran P. C., Blower T. R., Foulds I. J., Humphreys D. P., Lilley K. S. The phage abortive infection system, toxin, functions as a protein-RNA toxin-antitoxin pair. Proc Natl Acad Sci USA 2009; 106: 894-899.
41. 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 2012; 84: 979-989.
42. Wang X., Lord D. M., Cheng H. Y., Osbourne D. O., Hong S. H. A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat Chem Biol 2012; 8: 855-861.
43. Brooks T. M., Unterweger D., Bachmann V., Kostiuk B., Pukatzki S. Lytic activity of the Vibrio cholerae type VI secretion toxin VgrG-3 is inhibited by the antitoxin TsaB. J Biol Chem 2013; 288: 11: 7618-7625. Doi: 10.1074/jbc.M112.436725.
44. Chan W. T., Espinosa M., Yeo C. C. Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems. Front. Mol Biosci 2016; 3. Doi: 10.3389/fmolb.2016.00009.
45. Aakre C. D., Phung T. N., Huang D., Laub M.T. A bacterial toxin inhibits DNA replication elongation through a direct interaction with the в sliding clamp. Mol Cell 2013; 52: 5: 617-628. Doi: 10.1016/j.molcel.2013.10.014.
46. Wen Y., Behiels E., Devreese B. Toxin-Antitoxin systems: their role in persistence, biofilm formation, and pathogenicity. Pathog Dis 2014; 70: 3: 240-249. Doi: 10.1111/2049-632X.12145.
47. Unterholzner S. J., Poppenberger B., Rozhon W. Toxin-antitoxin systems: Biology, identification, and application. Mob Genet Elements 2013; 3. Doi: 10.4161/mge.26219.
48. Schuster C. F., Bertram R. Toxin-Antitoxin Systems of Staphylococcus aureus. Toxins (Basel) 2016; 8: 5: pii: E140. Doi: 10.3390/tox-ins8050140.
49. 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 2009; 5: 12: e1000767. Doi: 10.1371/journal.pgen.1000767.
50. Sala A., Bordes P., Genevaux P. Multiple toxin-antitoxin systems in Mycobacterium tuberculosis. Toxins 2014; 6: 1002-1020. Doi: 10.3390/toxins6031002.
51. Deter H. S., Jensen R. V., Mather W. H., Butzin N. C. Mechanisms for Differential Protein Production in Toxin-Antitoxin Systems. Toxins (Basel) 2017; 9: 7: pii: E211. Doi: 10.3390/toxins9070211.
52. Бухарин О.В. Персистенция бактериальных патогенов как физиологический феномен // Вестн. Моск. Ун-та. Сер 16. Биология. 2008; 1: 6-13.
53. Korch S. B., Henderson T. A., Hill T. M. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol Microbiol 2003; 50: 4: 1199-1213.
54. Du,rr T., Vulish M., Lewis K. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol 2010; 8: 2: e1000317. Doi: 10.1371/journal.pbio.1000317.
55. Verstraeten N., Knapen W. J., Fauvart M., Michiels J. Membrane depolarization-triggered responsive diversification leads to antibiotic tolerance. Microb Cell 2015; 2: 8: 299-301. Doi: 10.15698/mic2015.08.220.
56. Lobato-Morquez D., Moreno-Cyrdoba I., Figueroa V., Dnaz-Orejas R., Garcna-del Portillo F. Distinct type I and type II toxin-antitoxin modules control Salmonella lifestyle inside eukaryotic cells. Sci Rep 2015; 5: 9374. Doi: 10.1038/srep09374.
57. Chukwudi C. U., Good L. The role of the hok/sok locus in bacterial response to stressful growth conditions. Microb Pathog 2015; 79: 70-79. Doi: 10.1016/j.micpath.2015.01.009.
58. Sayed N., Nonin-Lecomte S., Rety S., Felden B. Functional and structural insights of a Staphylococcus aureus apoptotic-like membrane peptide from a toxin-antitoxin module. J Biol Chem 2012; 287: 43454-43463. Doi: 10.1074/jbc.M112.402693.
59. Sass P., Josten M., Famulla K., Schiffer G., Sahl H. G., Hamoen L., Brotz-Oesterhelt H. Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc Natl Acad Sci USA 2011; 108: 17474-17479. Doi: 10.1073/pnas.1110385108.
60. Leung E., Datti A., Cossette M., Goodreid J., McCaw S. E., Mah M., Nakhamchik A., Ogata K., El Bakkouri M., Cheng Y.Q. et al. Activators of cylindrical proteases as antimicrobials: Identification and development of small molecule activators of ClpP protease. Chem Biol 2011; 18: 1167-1178. Doi: 10.1016/j.chembiol.2011.07.023.
61. Williams J. J., Hergenrother P. J. Artificial activation of toxin-antitoxin systems as an antibacterial strategy. Trends Microbiol 2012; 20: 291-298. Doi: 10.1016/j.tim.2012.02.005.
62. Bienstock R. J. Computational drug design targeting protein-protein interactions. Curr Pharm Des 2012; 18: 1240-1254. Doi: 10.1111/j.1365-2731.2012.06564. x.
63. Justice S. S., Hunstad D. A., Cegelski L., Hultgren S. J. Morphological plasticity as a bacterial survival strategy. Nat Rev Microbiol 2008; 6: 162-168. Doi: 10.1038/nrmicro1820.
64. Mutschler H., Meinhart A. Epsilon/zeta systems: Their role in resistance, virulence, and their potential for antibiotic development. J Mol Med 2011; 89: 1183-1194. Doi: 10.1007/s00109-011-0797-4.
65. Zhang Y., Inouye M. RatA (YfjG), an Escherichia coli toxin, inhibits 70S ribosome association to block translation initiation. Mol Microbiol 2011; 79: 1418-1429. Doi: 10.1111/j.1365-2958.2010.07506. x.
66. Al Refaii A., Alix J. H. Ribosome biogenesis is temperature-dependent and delayed in Escherichia coli lacking the chaperones DnaK or DnaJ. Mol Microbiol 2009; 71: 748-762. Doi: 10.1111/j. 13652958.2008.06561. x.
67. Hall A. M., Gollan B., Helaine S. Toxin-antitoxin systems: reversible toxicity. Curr Opin Microbiol 2017; 36: 102-110. Doi: 10.1016/j.mib.2017.02.003.
68. Dao-Thi M. H., Charlier D., Loris R., Maes D., Messens J., Wyns L., Backmann J. Intricate interactions within the ccd plasmid addiction system. J. Biol Chem 2002; 277: 3733-3742. Doi: 10.1074/jbc.M105505200.
69. Mok W. W., Patel N. H., Li Y. Decoding toxicity: deducing the sequence requirements of IbsC, a type I toxin in Escherichia coli. J Biol Chem 2010; 285: 53: 41627-41636. Doi: 10.1074/jbc.M110.149179.
70. Fozo E. M., Kawano M., Fontaine F., Kaya Y., Mendieta K. S., Jones K. L., Ocampo A., Rudd K. E., Storz G. Repression of small toxic protein synthesis by the Sib and OhsC small RNAs. Mol Microbiol 2008; 70: 5: 1076-1093. Doi: 10.1111/j.1365-2958.2008.06394. x.
71. Vogel J., Argaman L., Wagner E. G., Altuvia S. The small RNA IstR inhibits synthesis of an SOS-induced toxic peptide. 2004; 14: 24: 2271-2276. Doi: 10.1016/j.cub.2004.12.003
72. Unoson C., Wagner E. G. A small SOS-induced toxin is targeted against the inner membrane in Escherichia coli. Mol Microbiol 2008; 70: 1: 258-270. Doi: 10.1111/j.1365-2958.2008.06416. x.
73. Vesper O., Amitai S., Belitsky M., Byrgazov K., Kaberdina A.C., Engelberg-Kulka H., Moll I. Selective translation of leaderless mRNAs by specialized ribosomes generated by MazF in Escherichia coli. Cell 2011; 147: 1: 147-157. Doi: 10.1016/j.cell.2011.07.047.
74. Budde P. P., Davis B. M., Yuan J., Waldor M. K. Characterization of a higBA toxin-antitoxin locus in Vibrio cholerae. J Bacteriol 2007; 189: 491-500. Doi: 10.1128/JB.00909-06.
75. 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 2009; 106: 3: 894-899. Doi: 10.1073/pnas.0808832106.
76. Aakre C. D., Phung T. N., Huang D., Laub M. T. A bacterial toxin inhibits DNA replication elongation through a direct interaction with the в sliding clamp. Mol Cell 2013; 52: 5: 617-628. Doi: 10.1016/j.mol-cel.2013.10.014.
77. Brielle R., Pinel-Marie M. L., Felden B. Linking bacterial type I toxins with their actions. Curr Opin Microbiol 2016; 30: 114-121. Doi: 10.1016/j.mib.2016.01.009.
78. Brantl S., Jahn N. sRNAs in bacterial type I and type III toxin-antitoxin systems. FEMS Microbiol Rev 2015; 39: 3: 413-427. Doi: 10.1093/femsre/fuv003.
79. Crofts T. S., Gasparrini A. J., Dantas G. Next-generation approaches to understand and combat the antibiotic resistome. Nature Reviews Microbiology 2017; 15: 422-434. Doi:10.1038/nrmicro.2017.28.
80. Gupta K., Tripathi A., Sahu A., Varadarajan R. Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance. J Bacteriol 2017; 199:19: pii: e00397-17. Doi: 10.1128/JB.00397-17.
81. Chan W. T, Balsa D., Espinosa M. One cannot rule them all: Are bacterial toxins-antitoxins druggable? FEMS Microbiol Rev 2015; 39: 522-540. Doi: 10.1093/femsre/fuv002.
82. Mruk I., Kobayashi I. To be or not to be: Regulation of restriction-mod-ification systems and other toxin-antitoxin systems. Nucleic Acids Res 2014; 42: 70-86. Doi: 10.1093/nar/gkt711.
83. Ainelo A., Tamman H., Leppik M., Remme J., Horak R. The toxin GraT inhibits ribosome biogenesis. Mol Microbiol 2016; 100: 719-734. Doi: 10.1111/mmi.13344. СВЕДЕНИЯ ОБ АВТОРАХ:
84. Shapiro S. Speculative strategies for new antibacterials: All roads should not lead to Rome. J Antibiot 2013; 66: 371-386. Doi: 10.1038/ja.2013.27.
85. Bienstock R. J. Computational drug design targeting protein-protein interactions. Curr Pharm Des 2012; 18: 9: 1240-1254.
86. Solecki O., Mosbah A., Baudy Floc’h M., Felden B. Converting a Staphylococcus aureus toxin into effective cyclic pseudopeptide antibiotics. Chem Biol 2015; 22: 329-335. Doi: 10.1016/j.chembiol.2014.12.016.
87. Huys I., Pirnay J. P., Lavigne R., Jennes S., De Vos D., Casteels M., Verbeken G. Paving a regulatory pathway for phage therapy. Europe should muster the resources to financially, technically and legally support the introduction of phage therapy. EMBO Rep 2013; 14: 951-954. Doi: 10.1038/embor.2013.163.
88. 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 2014; 343: 204-208.
Review
For citations:
Andryukov B.G., Besednova N.N., Zaporozhets T.S., Bynina M.P. Bacterial Toxin-Antitoxin Systems and New Strategies for Creating Antibacterial Preparations. Antibiot Khimioter = Antibiotics and Chemotherapy. 2018;63(3-4):50-58. (In Russ.)
Views:
562
Email this article 