The Biology of Persister Cells in Escherichia coli

  • Alexander HarmsEmail author


Bacterial persisters are dormant, antibiotic-tolerant cells that are phenotypic variants formed within a regularly growing, drug-susceptible population. They differ from genetically or phenotypically resistant cells in that their survival of antibiotic treatment is rooted in a dormant physiology and not in the obstruction of drug–target interactions. In this chapter, I assembled a concise overview of the formation, survival, and evolution of persisters formed by the model organism Escherichia coli. Though the formation of persister cells has stochastic aspects, it is often induced by starvation or stress as a specialized differentiation of part of the population (responsive diversification). Consequently, the phenotypic heterogeneity of persisters and regularly growing cells is commonly interpreted as a bet-hedging strategy that ensures population survival under the threat of catastrophic events and that at the same time optimizes the benefit from favorable conditions. Multiple different molecular mechanisms have been implicated in persister cell formation and can be grouped into two major classes. Non-specific mechanisms affect bacterial physiology on a global scale via, for example, alterations of energy metabolism, or are purely stochastic events that shut down cellular processes by an accidental malfunctioning (persistence as stuff happens). Conversely, specialized mechanisms directly inhibit antibiotic targets often through activation of fine-tuned molecular switches known as toxin-antitoxin modules. In addition, the repair of cellular damage caused by antibiotics is critical for the resuscitation of persister cells. A major obstacle to coherently interpreting these findings is the fragmented nature of the literature and several controversies that should be consolidated by future studies.


Antibiotic tolerance; Bacterial persister; Toxin-antitoxin module; Phenotypic heterogeneity 



The author is grateful to Prof. Kenn Gerdes, Prof. Urs Jenal, Dr. Szabolcs Semsey, and Dr. Pablo Manfredi for stimulating discussions about the elusive nature of genetically encoded antibiotic tolerance. This work was supported by Swiss National Science Foundation (SNSF) Ambizione Fellowship PZ00P3_180085.


  1. Abel Zur Wiesch, P., Abel, S., Gkotzis, S., Ocampo, P., Engelstadter, J., Hinkley, T., Magnus, C., Waldor, M. K., Udekwu, K., & Cohen, T. (2015). Classic reaction kinetics can explain complex patterns of antibiotic action. Science Translational Medicine, 7, 287ra73.PubMedCrossRefGoogle Scholar
  2. Aldred, K. J., Kerns, R. J., & Osheroff, N. (2014). Mechanism of quinolone action and resistance. Biochemistry, 53, 1565–1574.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Allison, K. R., Brynildsen, M. P., & Collins, J. J. (2011). Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature, 473, 216–220.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Amato, S. M., & Brynildsen, M. P. (2015). Persister heterogeneity arising from a single metabolic stress. Current Biology, 25, 2090–2098.PubMedCrossRefGoogle Scholar
  5. Amato, S. M., Orman, M. A., & Brynildsen, M. P. (2013). Metabolic control of persister formation in Escherichia coli. Molecular Cell, 50, 475–487.PubMedCrossRefGoogle Scholar
  6. Baharoglu, Z., & Mazel, D. (2014). SOS, the formidable strategy of bacteria against aggressions. FEMS Microbiology Reviews, 38, 1126–1145.PubMedCrossRefGoogle Scholar
  7. Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., & Leibler, S. (2004). Bacterial persistence as a phenotypic switch. Science, 305, 1622–1625.CrossRefGoogle Scholar
  8. Balaban, N. Q., Gerdes, K., Lewis, K., & Mckinney, J. D. (2013). A problem of persistence: Still more questions than answers? Nature Reviews. Microbiology, 11, 587–591.PubMedCrossRefGoogle Scholar
  9. Berghoff, B. A., & Wagner, E. G. H. (2017). RNA-based regulation in type I toxin-antitoxin systems and its implication for bacterial persistence. Current Genetics, 63, 1011–1016.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Berghoff, B. A., Hoekzema, M., Aulbach, L., & Wagner, E. G. (2017). Two regulatory RNA elements affect TisB-dependent depolarization and persister formation. Molecular Microbiology, 103, 1020–1033.PubMedCrossRefGoogle Scholar
  11. Bigger, J. (1944). Treatment of staphylococcal infections with penicillin by intermittent sterilisation. The Lancet, 244, 497–500.CrossRefGoogle Scholar
  12. Blango, M. G., & Mulvey, M. A. (2010). Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrobial Agents and Chemotherapy, 54, 1855–1863.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Brauner, A., Fridman, O., Gefen, O., & Balaban, N. Q. (2016). Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nature Reviews. Microbiology, 14, 320–330.PubMedCrossRefGoogle Scholar
  14. Cho, H., Uehara, T., & Bernhardt, T. G. (2014). Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell, 159, 1300–1311.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Claudi, B., Spröte, P., Chirkova, A., Personnic, N., Zankl, J., Schürmann, N., Schmidt, A., & Bumann, D. (2014). Phenotypic variation of Salmonella in host tissues delays eradication by antimicrobial chemotherapy. Cell, 158, 722–733.CrossRefGoogle Scholar
  16. 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. Nature Microbiology, 1, 16051.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Corona, F., & Martinez, J. L. (2013). Phenotypic resistance to antibiotics. Antibiotics (Basel), 2, 237–255.CrossRefGoogle Scholar
  18. Dörr, T., Lewis, K., & Vulić, M. (2009). SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genetics, 5, e1000760.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Dörr, T., Vulic, M., & Lewis, K. (2010). Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biology, 8, e1000317.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Dörr, T., Alvarez, L., Delgado, F., Davis, B. M., Cava, F., & Waldor, M. K. (2016). A cell wall damage response mediated by a sensor kinase/response regulator pair enables beta-lactam tolerance. Proceedings of the National Academy of Sciences of the United States of America, 113, 404–409.PubMedCrossRefGoogle Scholar
  21. El Meouche, I., Siu, Y., & Dunlop, M. J. (2016). Stochastic expression of a multiple antibiotic resistance activator confers transient resistance in single cells. Scientific Reports, 6, 19538.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Fauvart, M., De Groote, V. N., & Michiels, J. (2011). Role of persister cells in chronic infections: Clinical relevance and perspectives on anti-persister therapies. Journal of Medical Microbiology, 60, 699–709.PubMedCrossRefGoogle Scholar
  23. Fisher, R. A., Gollan, B., & Helaine, S. (2017). Persistent bacterial infections and persister cells. Nature Reviews. Microbiology, 15, 453–464.PubMedCrossRefGoogle Scholar
  24. Fridman, O., Goldberg, A., Ronin, I., Shoresh, N., & Balaban, N. Q. (2014). Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations. Nature, 513, 418–421.PubMedCrossRefGoogle Scholar
  25. Gohara, D. W., & Yap, M. F. (2018). Survival of the drowsiest: The hibernating 100S ribosome in bacterial stress management. Current Genetics, 64, 753–760.PubMedCrossRefGoogle Scholar
  26. Goneau, L. W., Yeoh, N. S., Macdonald, K. W., Cadieux, P. A., Burton, J. P., Razvi, H., & Reid, G. (2014). Selective target inactivation rather than global metabolic dormancy causes antibiotic tolerance in uropathogens. Antimicrobial Agents and Chemotherapy, 58, 2089–2097.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Goormaghtigh, F., & Van Melderen, L. (2016). Optimized method for measuring persistence in Escherichia coli with improved reproducibility. Methods in Molecular Biology, 1333, 43–52.PubMedCrossRefGoogle Scholar
  28. Goormaghtigh, F., Fraikin, N., Putrins, M., Hallaert, T., Hauryliuk, V., Garcia-Pino, A., Sjodin, A., Kasvandik, S., Udekwu, K., Tenson, T., Kaldalu, N., & Van Melderen, L. (2018a). Reassessing the role of type II toxin-antitoxin systems in formation of Escherichia coli type II persister cells. MBio, 9, e00640-18.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Goormaghtigh, F., Fraikin, N., Putrins, M., Hauryliuk, V., Garcia-Pino, A., Udekwu, K., Tenson, T., Kaldalu, N., & Van Melderen, L. (2018b). Reply to holden and errington, “Type II toxin-antitoxin systems and persister cells”. MBio, 9, e01838-18.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Gutierrez, A., Jain, S., Bhargava, P., Hamblin, M., Lobritz, M. A., & Collins, J. J. (2017). Understanding and sensitizing density-dependent persistence to quinolone antibiotics. Molecular Cell, 68, 1147–1154.e3.PubMedCrossRefGoogle Scholar
  31. Harms, A., Maisonneuve, E., & Gerdes, K. (2016). Mechanisms of bacterial persistence during stress and antibiotic exposure. Science, 354, aaf4268.CrossRefGoogle Scholar
  32. Harms, A., Fino, C., Sørensen, M. A., Semsey, S., & Gerdes, K. (2017). Prophages and growth dynamics confound experimental results with antibiotic-tolerant persister cells. MBio, 8, e01964-17.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Harms, A., Brodersen, D. E., Mitarai, N., & Gerdes, K. (2018). Toxins, targets, and triggers: An overview of toxin-antitoxin biology. Molecular Cell, 70, 768–784.PubMedCrossRefGoogle Scholar
  34. Hauryliuk, V., Atkinson, G. C., Murakami, K. S., Tenson, T., & Gerdes, K. (2015). Recent functional insights into the role of (p)ppGpp in bacterial physiology. Nature Reviews. Microbiology, 13, 298–309.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Helaine, S., Cheverton, A. M., Watson, K. G., Faure, L. M., Matthews, S. A., & Holden, D. W. (2014). Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science, 343, 204–208.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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 Microbiology, 13, 25.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Joers, A., Kaldalu, N., & Tenson, T. (2010). The frequency of persisters in Escherichia coli reflects the kinetics of awakening from dormancy. Journal of Bacteriology, 192, 3379–3384.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Johnson, P. J., & Levin, B. R. (2013). Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus. PLoS Genetics, 9, e1003123.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Kaldalu, N., Hauryliuk, V., & Tenson, T. (2016). Persisters-as elusive as ever. Applied Microbiology and Biotechnology, 100, 6545–6553.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Keren, I., Kaldalu, N., Spoering, A., Wang, Y., & Lewis, K. (2004a). Persister cells and tolerance to antimicrobials. FEMS Microbiology Letters, 230, 13–18.PubMedCrossRefGoogle Scholar
  41. Keren, I., Shah, D., Spoering, A., Kaldalu, N., & Lewis, K. (2004b). Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. Journal of Bacteriology, 186, 8172–8180.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Keren, I., Wu, Y., Inocencio, J., Mulcahy, L. R., & Lewis, K. (2013). Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science, 339, 1213–1216.PubMedCrossRefGoogle Scholar
  43. Kohanski, M. A., Dwyer, D. J., & Collins, J. J. (2010). How antibiotics kill bacteria: From targets to networks. Nature Reviews. Microbiology, 8, 423–435.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kotte, O., Volkmer, B., Radzikowski, J. L., & Heinemann, M. (2014). Phenotypic bistability in Escherichia coli’s central carbon metabolism. Molecular Systems Biology, 10, 736.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Krause, K. M., Serio, A. W., Kane, T. R., & Connolly, L. E. (2016). Aminoglycosides: An overview. Cold Spring Harbor Perspectives in Medicine, 6, a027029.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Laxminarayan, R., Duse, A., Wattal, C., Zaidi, A. K., Wertheim, H. F., Sumpradit, N., Vlieghe, E., Hara, G. L., Gould, I. M., Goossens, H., Greko, C., SO, A. D., Bigdeli, M., Tomson, G., Woodhouse, W., Ombaka, E., Peralta, A. Q., Qamar, F. N., Mir, F., Kariuki, S., Bhutta, Z. A., Coates, A., Bergstrom, R., Wright, G. D., Brown, E. D., & Cars, O. (2013). Antibiotic resistance-the need for global solutions. The Lancet Infectious Diseases, 13, 1057–1098.PubMedCrossRefGoogle Scholar
  47. Lee, A. J., Wang, S., Meredith, H. R., Zhuang, B., Dai, Z., & You, L. (2018). Robust, linear correlations between growth rates and beta-lactam-mediated lysis rates. Proceedings of the National Academy of Sciences of the United States of America, 115, 4069–4074.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Levin, B. R., & Rozen, D. E. (2006). Non-inherited antibiotic resistance. Nature Reviews. Microbiology, 4, 556–562.PubMedCrossRefGoogle Scholar
  49. Levin, B. R., Concepcion-Acevedo, J., & Udekwu, K. I. (2014). Persistence: A copacetic and parsimonious hypothesis for the existence of non-inherited resistance to antibiotics. Current Opinion in Microbiology, 21, 18–21.PubMedCrossRefGoogle Scholar
  50. Lewis, K. (2005). Persister cells and the riddle of biofilm survival. Biochemistry (Mosc), 70, 267–274.CrossRefGoogle Scholar
  51. Lewis, K. (2010). Persister cells. Annual Review of Microbiology, 64, 357–372.PubMedCrossRefGoogle Scholar
  52. Li, Y., & Zhang, Y. (2007). PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrobial Agents and Chemotherapy, 51, 2092–2099.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Li, J., Ji, L., Shi, W., Xie, J., & Zhang, Y. (2013). Trans-translation mediates tolerance to multiple antibiotics and stresses in Escherichia coli. The Journal of Antimicrobial Chemotherapy, 68, 2477–2481.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Liu, Y., & Imlay, J. A. (2013). Cell death from antibiotics without the involvement of reactive oxygen species. Science, 339, 1210–1213.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Luidalepp, H., Joers, A., Kaldalu, N., & Tenson, T. (2011). Age of inoculum strongly influences persister frequency and can mask effects of mutations implicated in altered persistence. Journal of Bacteriology, 193, 3598–3605.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 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 Microbiology Letters, 303, 33–40.PubMedCrossRefGoogle Scholar
  57. Maisonneuve, E., & Gerdes, K. (2014). Molecular mechanisms underlying bacterial persisters. Cell, 157, 539–548.PubMedCrossRefGoogle Scholar
  58. McKay, S. L., & Portnoy, D. A. (2015). Ribosome hibernation facilitates tolerance of stationary-phase bacteria to aminoglycosides. Antimicrobial Agents and Chemotherapy, 59, 6992–6999.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Michiels, J. E., Van Den Bergh, B., Verstraeten, N., Fauvart, M., & Michiels, J. (2016). In vitro emergence of high persistence upon periodic aminoglycoside challenge in the ESKAPE pathogens. Antimicrobial Agents and Chemotherapy, 60, 4630–4637.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Miller, C., Thomsen, L. E., Gaggero, C., Mosseri, R., Ingmer, H., & Cohen, S. N. (2004). SOS response induction by ß-lactams and bacterial defense against antibiotic lethality. Science, 305, 1629–1631.CrossRefGoogle Scholar
  61. Molina-Quiroz, R. C., Lazinski, D. W., Camilli, A., & Levy, S. B. (2016). Transposon-sequencing analysis unveils novel genes involved in the generation of persister cells in uropathogenic Escherichia coli. Antimicrobial Agents and Chemotherapy, 60, 6907–6910.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Mordukhova, E. A., & Pan, J. G. (2014). Stabilization of homoserine-O-succinyltransferase (MetA) decreases the frequency of persisters in Escherichia coli under stressful conditions. PLoS One, 9, e110504.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Moyed, H. S., & Bertrand, K. P. (1983). hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. Journal of Bacteriology, 155, 768–775.PubMedPubMedCentralGoogle Scholar
  64. Neidhardt, F. C. (2006). Apples, oranges and unknown fruit. Nature Reviews. Microbiology, 4, 876.PubMedCrossRefGoogle Scholar
  65. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Ocampo, P. S., Lazar, V., Papp, B., Arnoldini, M., Abel Zur Wiesch, P., Busa-Fekete, R., Fekete, G., Pal, C., Ackermann, M., & Bonhoeffer, S. (2014). Antagonism between bacteriostatic and bactericidal antibiotics is prevalent. Antimicrobial Agents and Chemotherapy, 58, 4573–4582.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Orman, M. A., & Brynildsen, M. P. (2013). Dormancy is not necessary or sufficient for bacterial persistence. Antimicrobial Agents and Chemotherapy, 57, 3230–3239.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Pennington, J. M., & Rosenberg, S. M. (2007). Spontaneous DNA breakage in single living Escherichia coli cells. Nature Genetics, 39, 797–802.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Pu, Y., Zhao, Z., Li, Y., Zou, J., Ma, Q., Zhao, Y., Ke, Y., Zhu, Y., Chen, H., Baker, M. A., Ge, H., Sun, Y., Xie, X. S., & BAI, F. (2016). Enhanced efflux activity facilitates drug tolerance in dormant bacterial cells. Molecular Cell, 62, 284–294.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Renggli, S., Keck, W., Jenal, U., & Ritz, D. (2013). Role of autofluorescence in flow cytometric analysis of Escherichia coli treated with bactericidal antibiotics. Journal of Bacteriology, 195, 4067–4073.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Schumacher, M. A., Balani, P., Min, J., Chinnam, N. B., Hansen, S., Vulic, M., Lewis, K., & Brennan, R. G. (2015). HipBA-promoter structures reveal the basis of heritable multidrug tolerance. Nature, 524, 59–64.PubMedCrossRefGoogle Scholar
  72. Shan, Y., Lazinski, D., Rowe, S., Camilli, A., & Lewis, K. (2015). Genetic basis of persister tolerance to aminoglycosides in Escherichia coli. MBio, 6, e00078-15.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Spoering, A. L., Vulic, M., & Lewis, K. (2006). GlpD and PlsB participate in persister cell formation in Escherichia coli. Journal of Bacteriology, 188, 5136–5144.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Stepanyan, K., Wenseleers, T., Duenez-Guzman, E. A., Muratori, F., Van Den Bergh, B., Verstraeten, N., De Meester, L., Verstrepen, K. J., Fauvart, M., & Michiels, J. (2015). Fitness trade-offs explain low levels of persister cells in the opportunistic pathogen Pseudomonas aeruginosa. Molecular Ecology, 24, 1572–1583.PubMedCrossRefGoogle Scholar
  76. Stewart, B., & Rozen, D. E. (2012). Genetic variation for antibiotic persistence in Escherichia coli. Evolution, 66, 933–939.PubMedCrossRefGoogle Scholar
  77. Theodore, A., Lewis, K., & Vulic, M. (2013). Tolerance of Escherichia coli to fluoroquinolone antibiotics depends on specific components of the SOS response pathway. Genetics, 195, 1265–1276.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Van Den Bergh, B., Michiels, J. E., Wenseleers, T., Windels, E. M., Boer, P. V., Kestemont, D., De Meester, L., Verstrepen, K. J., Verstraeten, N., Fauvart, M., & Michiels, J. (2016). Frequency of antibiotic application drives rapid evolutionary adaptation of Escherichia coli persistence. Nature Microbiology, 1, 16020.PubMedCrossRefGoogle Scholar
  79. Van Den Bergh, B., Fauvart, M., & Michiels, J. (2017). Formation, physiology, ecology, evolution and clinical importance of bacterial persisters. FEMS Microbiology Reviews, 41, 219–251.PubMedCrossRefGoogle Scholar
  80. Van Melderen, L., & Wood, T. K. (2017). Commentary: What is the link between stringent response, endoribonuclease encoding type II toxin-antitoxin systems and persistence? Frontiers in Microbiology, 8, 191.PubMedPubMedCentralGoogle Scholar
  81. Vazquez-Laslop, N., Lee, H., & Neyfakh, A. A. (2006). Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. Journal of Bacteriology, 188, 3494–3497.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Veening, J. W., Smits, W. K., & Kuipers, O. P. (2008). Bistability, epigenetics, and bet-hedging in bacteria. Annual Review of Microbiology, 62, 193–210.PubMedCrossRefGoogle Scholar
  83. Vega, N. M., Allison, K. R., Khalil, A. S., & Collins, J. J. (2012). Signaling-mediated bacterial persister formation. Nature Chemical Biology, 8, 431–433.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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., Versees, W., Hofkens, J., Jansen, M., Fauvart, M., & Michiels, J. (2015). Obg and membrane depolarization are part of a microbial bet-hedging strategy that leads to antibiotic tolerance. Molecular Cell, 59, 9–21.PubMedCrossRefGoogle Scholar
  85. Völzing, K. G., & Brynildsen, M. P. (2015). Stationary-phase persisters to ofloxacin sustain DNA damage and require repair systems only during recovery. MBio, 6, e00731–e00715.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Wakamoto, Y., Dhar, N., Chait, R., Schneider, K., Signorino-Gelo, F., Leibler, S., & Mckinney, J. D. (2013). Dynamic persistence of antibiotic-stressed mycobacteria. Science, 339, 91–95.PubMedCrossRefGoogle Scholar
  87. Wilmaerts, D., Bayoumi, M., Dewachter, L., Knapen, W., Mika, J. T., Hofkens, J., Dedecker, P., Maglia, G., Verstraeten, N., & Michiels, J. (2018). The persistence-inducing toxin HokB forms dynamic pores that cause ATP leakage. MBio, 9, e00744-18.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Wiuff, C., & Andersson, D. I. (2007). Antibiotic treatment in vitro of phenotypically tolerant bacterial populations. The Journal of Antimicrobial Chemotherapy, 59, 254–263.PubMedCrossRefGoogle Scholar
  89. Wood, T. K., Knabel, S. J., & Kwan, B. W. (2013). Bacterial persister cell formation and dormancy. Applied and Environmental Microbiology, 79, 7116–7121.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Yang, J. H., Bening, S. C., & Collins, J. J. (2017). Antibiotic efficacy-context matters. Current Opinion in Microbiology, 39, 73–80.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Biozentrum, University of BaselBaselSwitzerland

Personalised recommendations