Molecular Biology

, Volume 53, Issue 4, pp 475–483 | Cite as

Molecular Mechanisms of Non-Inherited Antibiotic Tolerance in Bacteria and Archaea

  • T. M. KhlebodarovaEmail author
  • V. A. Likhoshvai


The phenomenon of bacterial persistence, also known as non-inherited antibiotic tolerance in a part of bacterial populations, was described more than 70 years ago. This type of tolerance contributes to the chronization of infectious diseases, including tuberculosis. Currently, the emergence of persistent cells in bacterial populations is associated with the functioning of some stress-induced molecular triggers, including toxin–antitoxin systems. In the presented review, genetic and metabolic peculiarities of persistent cells are considered and the mechanisms of their occurrence are discussed. The hypothesis of the origin of persister cells based on bistability, arising due to the non-linear properties of a coupled transcription–translation system, was proposed. Within this hypothesis, the phenomenon of the bacterial persistence of modern cells is considered as a result of the genetic fixation of the phenotypic multiplicity that emerged in primitive cells in the process of neutrally coupled co-evolution (genetic drift of multiple neutrally coupled mutations). Our hypothesis explains the properties of persister cells, as well as their origin and “ineradicable” nature.


molecular trigger cell cycle phenotypic multiplicity bacterial persistence neutrally coupled co-evolution modeling 



This work was supported by the Program of Fundamental Studies of the Siberian Branch, Russian Academy of Sciences (project no. 0324-2019-0040).


Conflict of interest. The authors declare that they have no conflict of interest.

Statement of the welfare of animals. This article does not contain any studies involving animals or human participants performed by any of the authors.


  1. 1.
    Dhar N., McKinney J.D. 2007. Microbial phenotypic heterogeneity and antibiotic tolerance. Curr. Opin. Microbiol. 10, 30–38.CrossRefPubMedGoogle Scholar
  2. 2.
    Lewis K. 2007. Persister cells, dormancy and infectious disease. Nat. Rev. Microbiol. 5, 48–56.CrossRefPubMedGoogle Scholar
  3. 3.
    Lewis K. 2008. Multidrug tolerance of biofilms and persister cells. Curr. Top. Microbiol. Immunol. 322, 107–131.PubMedGoogle Scholar
  4. 4.
    Lewis K. 2012. Persister cells: Molecular mechanisms related to antibiotic tolerance. Handb. Exp. Pharmacol. 211, 121–133.CrossRefGoogle Scholar
  5. 5.
    Jayaraman R. 2008. Bacterial persistence: Some new insights into an old phenomenon. J. Biosci. 33, 795–805.CrossRefPubMedGoogle Scholar
  6. 6.
    Kint C.I., Verstraeten N., Fauvart M., Michiels J. 2012. New-found fundamentals of bacterial persistence. Trends Microbiol. 20, 577–585.CrossRefPubMedGoogle Scholar
  7. 7.
    Amato S.M., Fazen C.H., Henry T.C., Mok W.W., Orman M.A., Sandvik E.L., Volzing K.G., Brynildsen M.P. 2014. The role of metabolism in bacterial persistence. Front. Microbiol. 5, 70.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kester J.C., Fortune S.M. 2014. Persisters and beyond: Mechanisms of phenotypic drug resistance and drug tolerance in bacteria. Crit. Rev. Biochem. Mol. Biol. 49, 91–101.CrossRefPubMedGoogle Scholar
  9. 9.
    Gerdes K., Semsey S. 2016. Pumping persisters. Nature. 534, 41–42.CrossRefPubMedGoogle Scholar
  10. 10.
    Conlon B.P., Rowe S.E., Gandt A.B., Nuxoll A.S., Donegan N.P., Zalis E.A., Clair G., Adkins J.N., Cheung A.L., Lewis K. 2016. Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat. Microbiol. 1, 16051.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Defraine V., Fauvart M., Michiels J. 2018. Fighting bacterial persistence: Current and emerging anti-persister strategies and therapeutics. Drug Resist. Update. 38, 12–26.CrossRefGoogle Scholar
  12. 12.
    Wood T.K., Knabel S.J., Kwan B.W. 2013. Bacterial persister cell formation and dormancy. Appl. Environ. Microbiol. 79, 7116–7121.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bigger J.W. 1944. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet. 244, 497–500.CrossRefGoogle Scholar
  14. 14.
    Lederberg J., Lederberg E.M. 1952. Replica plating and indirect selection of bacterial mutants. J. Bacteriol. 63, 399–406.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Moyed H.S., Bertrand K.P. 1983. hipA, a newly recognized gene of Escherichia coli K12 that affects the frequency of persisters after inhibition of murein synthesis. J. Bacteriol. 155, 768–775.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Balaban N.Q., Merrin J., Chait R., Kowalik L., Leibler S. 2004. Bacterial persistence as a phenotypic switch. Science. 305, 1622–1625.CrossRefPubMedGoogle Scholar
  17. 17.
    Keren I., Shah D., Spoering A., Kaldalu N., Lewis K. 2004. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 186, 8172–8180.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Shah D., Zhang Z., Khodursky A., Kaldalu N., Kurg K., Lewis K. 2006. Persisters: A distinct physiological state of E. coli. BMC Microbiol. 6, 53.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Radzikowski J.L., Vedelaar S., Siegel D., Ortega Á.D., Schmidt A., Heinemann M. 2016. Bacterial persistence is an active σS stress response to metabolic flux limitation. Mol. Syst. Biol. 12, 882.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nguyen D., Joshi-Datar A., Lepine F., Bauerle E., Olakanmi O., Beer K., McKay G., Siehnel R., Schafhauser J., Wang Y., Britigan B.E., Singh P.K. 2011. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science. 334, 982–986.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Grant S.S., Hung D.T. 2013. Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response. Virulence. 4, 273–283.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Grant S.S., Kaufmann B.B., Chand N.S., Haseley N., Hung D.T. 2012. Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proc. Natl. Acad. Sci. U. S. A. 109, 12147–12152.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Shapiro J.A., Nguyen V.L., Chamberlain N.R. 2011. Evidence for persisters in Staphylococcus epidermidis RP62a planktonic cultures and biofilms. J. Med. Microbiol. 60, 950–960.CrossRefPubMedGoogle Scholar
  24. 24.
    Bernier S.P., Lebeaux D., DeFrancesco A.S., Valomon A., Soubigou G., Coppée J.Y., Ghigo J.M., Beloin C. 2013. Starvation, together with the SOS response, mediates high biofilm-specific tolerance to the fluoroquinolone ofloxacin. PLoS Genet. 9, e1003144.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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., Marchal K., Beirlant J., Versqes W., Hofkens J., Jansen M., et al. 2015. Obg and membrane depolarization are part of a microbial bet-hedging strategy that leads to antibiotic tolerance. Mol. Cell. 59, 9–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Grassi L., Di Luca M., Maisetta G., Rinaldi A.C., Esin S., Trampuz A., Batoni G. 2017. Generation of persister cells of Pseudomonas aeruginosa and Staphylococcus aureus by chemical treatment and evaluation of their susceptibility to membrane-targeting agents. Front. Microbiol. 8, 1917.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Megaw J., Gilmore B.F. 2017. Archaeal persisters: Persister cell formation as a stress response in Haloferax volcanii. Front. Microbiol. 8, 1589.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ferrell J.E. Jr. 2002. Self-perpetuating states in signal transduction: Positive feedback, double-negative feedback and bistability. Curr. Opin. Cell. Biol. 14, 140–148.CrossRefPubMedGoogle Scholar
  29. 29.
    Angeli D., Ferrell J.E. Jr., Sontag E.D. 2004. Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems. Proc. Natl. Acad. Sci. U. S. A. 101, 1822–1827.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ozbudak E.M., Thattai M., Lim H.N., Shraiman B.I., Van Oudenaarden A. 2004. Multistability in the lactose utilization network of Escherichia coli. Nature. 427, 737–740.CrossRefPubMedGoogle Scholar
  31. 31.
    Smits W.K., Kuipers O.P., Veening J.W. 2006. Phenotypic variation in bacteria: The role of feedback regulation. Nat. Rev. Microbiol. 4, 259–271.CrossRefPubMedGoogle Scholar
  32. 32.
    Dubnau D., Losick R. 2006. Bistability in bacteria. Mol. Microbiol. 61, 564–572.CrossRefPubMedGoogle Scholar
  33. 33.
    Piggot P. 2010. Epigenetic switching: Bacteria hedge bets about staying or moving. Curr. Biol. 20, R480–R482.CrossRefPubMedGoogle Scholar
  34. 34.
    Avendaño M.S., Leidy C., Pedraza J.M. 2013. Tuning the range and stability of multiple phenotypic states with coupled positive-negative feedback loops. Nat. Commun. 4, 2605.CrossRefPubMedGoogle Scholar
  35. 35.
    Kaern M., Elston T.C., Blake W.J., Collins J.J. 2005. Stochasticity in gene expression: From theories to phenotypes. Nat. Rev. Genet. 6, 451–464.CrossRefPubMedGoogle Scholar
  36. 36.
    Sureka K., Ghosh B., Dasgupta A., Basu J., Kundu M., Bose I. 2008. Positive feedback and noise activate the stringent response regulator rel in mycobacteria. PLoS One. 3, e1771.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    To T.L., Maheshri N. 2010. Noise can induce bimodality in positive transcriptional feedback loops without bistability. Science. 327, 1142–1145.CrossRefPubMedGoogle Scholar
  38. 38.
    Zheng X.D., Yang X.Q., Tao Y. 2011. Bistability, probability transition rate and first-passage time in an autoactivating positive-feedback loop. PLoS One. 6, e17104.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shu C.C., Chatterjee A., Dunny G., Hu W.S., Ramkrishna D. 2011. Bistability versus bimodal distributions in gene regulatory processes from population balance. PLoS Comput. Biol. 7, e1002140.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ghosh S., Banerjee S., Bose I. 2012. Emergent bistability: Effects of additive and multiplicative noise. Eur. Phys. J. E. Soft. Matter. 35, 11.CrossRefPubMedGoogle Scholar
  41. 41.
    Thomas P., Popović N., Grima R. 2014. Phenotypic switching in gene regulatory networks. Proc. Natl. Acad. Sci. U. S. A. 111, 6994–6999.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Dörr T., Vulić M., Lewis K. 2010. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol. 8, e1000317.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Tripathi A., Dewan P.C., Siddique S.A., Varadarajan R. 2014. MazF-induced growth inhibition and persister generation in Escherichia coli. J. Biol. Chem. 289, 4191–4205.CrossRefPubMedGoogle Scholar
  44. 44.
    Schumacher M.A., Balani P., Min J., Chinnam N.B., Hansen S., Vulić M., Lewis K., Brennan R.G. 2015. HipBA-promoter structures reveal the basis of heritable multidrug tolerance. Nature. 524 (7563), 59–64.CrossRefPubMedGoogle Scholar
  45. 45.
    Gerdes K., Christensen S.K., Løbner-Olesen A. 2005. Prokaryotic toxin-antitoxin stress response loci. Nat. Rev. Microbiol. 3, 371–382.CrossRefPubMedGoogle Scholar
  46. 46.
    Otsuka Y. 2016. Prokaryotic toxin-antitoxin systems: Novel regulations of the toxins. Curr. Genet. 62, 379–382.CrossRefPubMedGoogle Scholar
  47. 47.
    Soo V.W., Cheng H.Y., Kwan B.W., Wood T.K. 2014. De novo synthesis of a bacterial toxin/antitoxin system. Sci. Rep. 4, 4807.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lou C., Li Z., Ouyang Q. 2008. A molecular model for persister in E. coli. J. Theor. Biol. 255, 205–209.CrossRefPubMedGoogle Scholar
  49. 49.
    Koh R.S., Dunlop M.J. 2012. Modeling suggests that gene circuit architecture controls phenotypic variability in a bacterial persistence network. BMC Syst. Biol. 6, 47.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Feng J., Kessler D.A., Ben-Jacob E., Levine H. 2014. Growth feedback as a basis for persister bistability. Proc. Natl. Acad. Sci. U. S. A. 111, 544–549.CrossRefPubMedGoogle Scholar
  51. 51.
    Fasani R.A., Savageau M.A. 2013. Molecular mechanisms of multiple toxin-antitoxin systems are coordinated to govern the persister phenotype. Proc. Natl. Acad. Sci. U. S. A. 110, E2528–E2537.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gelens L., Hill L., Vandervelde A., Danckaert J., Loris R. 2013. A general model for toxin–antitoxin module dynamics can explain persister cell formation in E. coli. PLoS Comput. Biol. 9, e1003190.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Unterholzner S.J., Poppenberger B., Rozhon W. 2013. Toxin–antitoxin systems: Biology, identification, and application. Mob. Genet. Elements. 3, e26219.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Gupta K., Tripathi A., Sahu A., Varadarajan R. 2017. Contribution of the chromosomal ccdAB operon to bacterial drug tolerance. J. Bacteriol. 199, e00397-17.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Gurnev P.A., Ortenberg R., Dörr T., Lewis K., Bezrukov S.M. 2012. Persister promoting bacterial toxin TisB produces anion-selective pores in planar lipid bilayers. FEBS Lett. 586, 2529–2534.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    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.CrossRefPubMedGoogle Scholar
  57. 57.
    Maisonneuve E., Castro-Camargo M., Gerdes K. 2013. (p)ppGpp controls bacterial persistence by stochastic induction of toxin–antitoxin activity. Cell. 154, 1140–1150.CrossRefPubMedGoogle Scholar
  58. 58.
    Wu Y., Vulić M., Keren I., Lewis K. 2012. Role of oxidative stress in persister tolerance. Antimicrob. Agents Chemother. 56, 4922–4926.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Molina-Quiroz R.C., Silva-Valenzuela C., Brewster J., Castro-Nallar E., Levy S.B., Camilli A. 2018. Cyclic AMP regulates bacterial persistence through repression of the oxidative stress response and SOS-dependent DNA repair in uropathogenic Escherichia coli. MBio. 9, e02144-17.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Amato S.M., Brynildsen M.P. 2015. Persister heterogeneity arising from a single metabolic stress. Curr. Biol. 25, 2090–2098.CrossRefPubMedGoogle Scholar
  61. 61.
    Amato S.M., Orman M.A., Brynildsen M.P. 2013. Metabolic control of persister formation in Escherichia coli. Mol. Cell. 50, 475–487.CrossRefPubMedGoogle Scholar
  62. 62.
    Kotte O., Volkmer B., Radzikowski J.L., Heinemann M. 2014. Phenotypic bistability in Escherichia coli’s central carbon metabolism. Mol. Syst. Biol. 10, 736.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Namugenyi S.B., Aagesen A.M., Elliott S.R., Tischler A.D. 2017. Mycobacterium tuberculosis PhoY proteins promote persister formation by mediating Pst/SenX3-RegX3 phosphate sensing. MBio. 8, e00494-17.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Shan Y., Brown Gandt A., Rowe S.E., Deisinger J.P., Conlon B.P., Lewis K. 2017. ATP-dependent persister formation in Escherichia coli. MBio. 8, e02267-16.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Cameron D.R., Shan Y., Zalis E.A., Isabella V., Lewis K. 2018. A genetic determinant of persister cell formation in bacterial pathogens. J. Bacteriol. 200, e00303-18.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ghosh S., Sureka K., Ghosh B., Bose I., Basu J., Kundu M. 2011. Phenotypic heterogeneity in mycobacterial stringent response. BMC Syst. Biol. 5, 18.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Li Y., Zhang Y. 2007. PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrob. Agents Chemother. 51, 2092–2099.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Shi W., Zhang Y. 2010. PhoY2 but not PhoY1 is the PhoU homologue involved in persisters in Mycobacterium tuberculosis. J. Antimicrob. Chemother. 65, 1237–1242.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Ma C., Sim S., Shi W., Du L., Xing D., Zhang Y. 2010. Energy production genes sucB and ubiF are involved in persister survival and tolerance to multiple antibiotics and stresses in Escherichia coli. FEMS Microbiol. Lett. 303, 33–40.CrossRefPubMedGoogle Scholar
  70. 70.
    Torrey H.L., Keren I., Via L.E., Lee J.S., Lewis K. 2016. High persister mutants in Mycobacterium tuberculosis. PLoS One. 11, e0155127.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Kim J.S., Cho D.H., Heo P., Jung S.C., Park M., Oh E.J., Sung J., Kim P.J., Lee S.C., Lee D.H., Lee S., Lee C.H., Shin D., Jin Y.S., Kweon D.H. 2016. Fumarate-mediated persistence of Escherichia coli against antibiotics. Antimicrob. Agents Chemother. 60, 2232–2240.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Cui P., Niu H., Shi W., Zhang S., Zhang W., Zhang Y. 2018. Identification of genes involved in bacteriostatic antibiotic-induced persister formation. Front. Microbiol. 9, 413.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Wang Y., Bojer M.S., George S.E., Wang Z., Jensen P.R., Wolz C., Ingmer H. 2018. Inactivation of TCA cycle enhances Staphylococcus aureus persister cell formation in stationary phase. Sci. Rep. 8, 10849.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Hansen S., Lewis K., Vulic M. 2008. Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrob. Agents Chemother. 52, 2718–2726.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Hofsteenge N., van Nimwegen E., Silander O.K. 2013. Quantitative analysis of persister fractions suggests different mechanisms of formation among environmental isolates of E. coli. BMC Microbiol. 13, 25.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Kwan B.W., Valenta J.A., Benedik M.J., Wood T.K. 2013. Arrested protein synthesis increases persister-like cell formation. Antimicrob. Agents Chemother. 57, 1468–1473.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Likhoshvai V.A., Kogai V.V., Fadeev S.I., Khlebodarova T.M. 2016. Chaos and hyperchaos in a model of ribosome autocatalytic synthesis. Sci. Rep. 6, 38870.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Day T. 2016. Interpreting phenotypic antibiotic tolerance and persister cells as evolution via epigenetic inheritance. Mol. Ecol. 25, 1869–1882.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Likhoshvai V.A., Khlebodarova T.M. 2016. Phenotypic multiplicity of the bacterial cell cycle: A mathematical model. Mat. Biol. Bioinform. 11, 91–113.CrossRefGoogle Scholar
  80. 80.
    Schaechter M., Maaloe O., Kjeldgaard N.O. 1958. Dependency on medium and temperature of cell size and chemical composition during balanced grown of Salmonella typhimurium. J. Gen. Microbiol. 19, 592–606.CrossRefPubMedGoogle Scholar
  81. 81.
    Khlebodarova T.M., Likhoshvai V.A. 2016. Phenotypic multiplicity of the cell cycle: A consequence of unique properties of the coupled transcription–translation system. In: Matematicheskaya biologiya i bioinformatika (Mathematical Biology and Bioinformatics), vol. 6. Ed. Lakhno V.D. Moscow: MAKS Press, pp. 98–99.Google Scholar
  82. 82.
    Khlebodarova T.M., Likhoshvai V.A. 2018. Persister cells – a plausible outcome of neutral coevolutionary drift. Sci. Rep. 8, 14309.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Kimura M. 1968. Evolutionary rate at the molecular level. Nature. 217, 624–626.CrossRefPubMedGoogle Scholar
  84. 84.
    Kimura M. 1991. The neutral theory of molecular evolution: A review of recent evidence. Jpn. J. Genet. 66, 367–386.CrossRefPubMedGoogle Scholar
  85. 85.
    King J.L., Jukes T.H. 1969. Non-Darwinian evolution. Science. 164, 788–798.CrossRefPubMedGoogle Scholar
  86. 86.
    Ohta T. 2002. Near-neutrality in evolution of genes and gene regulation. Proc. Natl. Acad. Sci. U. S. A. 99, 16134–16137.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Ohta T. 1973. Slightly deleterious mutant substitutions in evolution. Nature. 246, 96–98.CrossRefPubMedGoogle Scholar
  88. 88.
    Koonin E.V. 2016. Splendor and misery of adaptation, or the importance of neutral null for understanding evolution. BMC Biol. 14, 114.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Volkenstein M.V. 1985. Biopolymers and evolution. Mol. Biol. (Moscow). 19, 55–66.Google Scholar
  90. 90.
    Volkenstein M.V., Goldstein B.N. 1986. Enzymatic mechanisms for compensating deleterious mutations. Mol. Biol. (Moscow). 20, 1645–1654.Google Scholar
  91. 91.
    Michaelis L., Menten M.L. 1913. Die Kinetik der Invertinwirkung. Biochem. Z. 49, 333–369.Google Scholar
  92. 92.
    Michaelis L., Menten M.M. 2013. The kinetics of invertin action. 1913. FEBS Lett. 587, 2712–2720.CrossRefPubMedGoogle Scholar
  93. 93.
    Schmalhausen I.I. 1968. Faktory evolyutsii: teoriya stabiliziruyushchego otbora (Factors of Evolution: The Theory of Stabilizing Selection). Eds. Berg R.L., Makhotin A.A., Yablokov A.V., Moscow: Nauka.Google Scholar
  94. 94.
    Kimura M. 1985. The role of compensatory neutral mutations in molecular evolution. J. Genet. 64, 7–19.CrossRefGoogle Scholar
  95. 95.
    Belinky F., Rogozin I.B., Koonin, E.V. 2017. Selection on start codons in prokaryotes and potential compensatory nucleotide substitutions. Sci. Rep. 7, 12422.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Frenkel-Morgenstern M., Tworowski D., Klipcan L., Safro M. 2009. Intra-protein compensatory mutations analysis highlights the tRNA recognition regions in aminoacyl-tRNA synthetases. J. Biomol. Struct. Dyn. 27, 115–126.CrossRefPubMedGoogle Scholar
  97. 97.
    DiNardo S., Voelkel K.A., Sternglanz R., Reynolds A.E., Wright A. 1982. Escherichia coli DNA topoisomerase I mutants have compensatory mutations in DNA gyrase genes. Cell. 31, 43–51.CrossRefPubMedGoogle Scholar
  98. 98.
    Pruss G.J., Manes S.H., Drlica K. 1982. Escherichia coli DNA topoisomerase I mutants: Increased supercoiling is corrected by mutations near gyrase genes. Cell. 31, 35–42.CrossRefPubMedGoogle Scholar
  99. 99.
    Raji A., Zabel D.J., Laufer C.S., Depew R.E. 1985. Genetic analysis of mutations that compensate for loss of Escherichia coli DNA topoisomerase I. J. Bacteriol. 162, 1173–1179.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Mao Y., Li Q., Zhang Y., Zhang J., Wei G., Tao S. 2013. Genome-wide analysis of selective constraints on high stability regions of mRNA reveals multiple compensatory mutations in Escherichia coli. PLoS One. 8, e73299.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Likhoshvai V.A., Khlebodarova T.M. 2018. One genotype → two phenotypes: “Neutrally coupled coevolution” and origin of persister cells. In: Matematicheskaya biologiya i bioinformatika (Mathematical Biology and Bioinformatics), vol. 7. Ed. Lakhno V.D. Pushchino: IMBP RAN, e67.Google Scholar
  102. 102.
    Likhoshvai V.A., Matushkin Yu.G. 2004. Sporadic emergence of latent phenotype during evolution. In: Bioinformatics of Genome Regulation and Structure. Eds. Kolchanov N., Hofestaedt R. Boston: Kluwer, pp. 231–243.Google Scholar
  103. 103.
    Germain E., Roghanian M., Gerdes K., Maisonneuve E. 2015. Stochastic induction of persister cells by HipA through (p)ppGpp-mediated activation of mRNA endonucleases. Proc. Natl. Acad. Sci. U. S. A. 112, 5171–5176.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Klapper I., Gilbert P., Ayati B.P., Dockery J., Ste-wart P.S. 2007. Senescence can explain microbial persistence. Microbiology. 153, 3623–3630.CrossRefPubMedGoogle Scholar
  105. 105.
    Shearwin K. 2009. Slow growth leads to a switch. Nat. Chem. Biol. 5, 784–785.CrossRefPubMedGoogle Scholar
  106. 106.
    Haney P.J., Badger J.H., Buldak G.L., Reich C.I., Woese C.R., Olsen G.J. 1999. Thermal adaptation analyzed by comparison of protein sequences from mesophilic and extremely thermophilic Methanococcus species. Proc. Natl. Acad. Sci. U. S. A. 96, 3578–3583.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Makarova K.S., Omelchenko M.V., Gaidamakova E.K., Matrosova V.Y, Vasilenko A., Zhai M., Lapidus A., Copeland A., Kim E., Land M., Mavrommatis K., Pitluck S., Richardson P.M., Detter C., Brettin T., et al. 2007. Deinococcus geothermalis: The pool of extreme radiation resistance genes shrinks. PLoS One. 2, e955.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Omelchenko M.V., Wolf Y.I., Gaidamakova E.K., Matrosova V.Y., Vasilenko A., Zhai M., Daly M.J., Koonin E.V., Makarova K.S. 2005. Comparative genomics of Thermus thermophilus and Deinococcus radiodurans: Divergent routes of adaptation to thermophily and radiation resistance. BMC Evol. Biol. 5, 57.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Kunin E.V. (2014) Logika sluchaya. O prirode i proiskhozhdenii biologicheskoi evolyutsii (The Logic of Occurrence. On the Nature and Origin of Biological Evolution). Moscow: Tsentrpoligraf.Google Scholar
  110. 110.
    Bernander R., Poplawski A. 1997. Cell cycle characteristics of thermophilic archaea. J. Bacteriol. 179, 4963–4969.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Tan I.S., Ramamurthi K.S. 2014. Spore formation in Bacillus subtilis. Environ. Microbiol. Rep. 6, 212–225.CrossRefPubMedGoogle Scholar

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© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  1. 1.Institute of Cytology and Genetics, Siberian Branch, Russian Academy of SciencesNovosibirskRussia

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