Biochemistry (Moscow)

, Volume 70, Issue 2, pp 267–274 | Cite as

Persister cells and the riddle of biofilm survival

  • K. Lewis


This review addresses a long standing puzzle in the life and death of bacterial populations—the existence of a small fraction of essentially invulnerable cells. Bacterial populations produce persisters, cells that neither grow nor die in the presence of bactericidal agents, and thus exhibit multidrug tolerance (MDT). The mechanism of MDT and the nature of persisters, which were discovered in 1944, have remained elusive. Our research has shown that persisters are largely responsible for the recalcitrance of infections caused by bacterial biofilms. The majority of infections in the developed world are caused by biofilms, which sparked a renewed interest in persisters. We developed a method to isolate persister cells, and obtained a gene expression profile of Escherichia coli persisters. The profile indicated an elevated expression of toxin-antitoxin modules and other genes that can block important cellular functions such as translation. Bactericidal antibiotics kill cells by corrupting the target function, such as translation. For example, aminoglycosides interrupt translation, producing toxic peptides. Inhibition of translation leads to a shutdown of other cellular functions as well, preventing antibiotics from corrupting their targets, which will give rise to tolerant persister cells. Overproduction of chromosomally-encoded “toxins” such as RelE, an inhibitor of translation, or HipA, causes a sharp increase in persisters. Deletion of the hipBA module produces a sharp decrease in persisters in both stationary and biofilm cells. HipA is thus the first validated persister/MDT gene. We conclude that the function of “toxins” is the exact opposite of the term, namely, to protect the cell from lethal damage. It appears that stochastic fluctuations in the levels of MDT proteins lead to formation of rare persister cells. Persisters are essentially altruistic cells that forfeit propagation in order to ensure survival of kin cells in the presence of lethal factors.

Key words

persisters multidrug tolerance biofilms death survival altruism 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Licking, E. (1999) Business Week, 98–100.Google Scholar
  2. 2.
    Lewis, K., Salyers A., Taber H., and Wax, R. (2001) Bacterial Resistance to Antimicrobials: Mechanisms, Genetics, Medical Practice and Public Health, Marcel Dekker, New York.Google Scholar
  3. 3.
    Tuomanen, E., Cozens, R., Tosch, W., Zak, O., and Tomasz, A. (1986) J. Gen. Microbiol., 132, 1297–1304.PubMedGoogle Scholar
  4. 4.
    Gilbert, P., Collier, P. J., and Brown, M. R. (1990) Antimicrob. Agents Chemother., 34, 1865–1868.PubMedGoogle Scholar
  5. 5.
    Gordon, C. A., Hodges, N. A., and Marriott, C. (1988) J. Antimicrob. Chemother., 22, 667–674.PubMedGoogle Scholar
  6. 6.
    Nichols, W. W., Dorrington, S. M., Slack, M. P., and Walmsley, H. L. (1988) Antimicrob. Agents Chemother., 32, 518–523.PubMedGoogle Scholar
  7. 7.
    Hoyle, B. D., Jass, J., and Costerton, J. W. (1990) J. Antimicrob. Chemother., 26, 1–5.PubMedGoogle Scholar
  8. 8.
    Shigeta, M., Tanaka, G., Komatsuzawa, H., Sugai, M., Suginaka, H., and Usui, T. (1997) Chemotherapy, 43, 340–345.PubMedCrossRefGoogle Scholar
  9. 9.
    Ishida, H., Ishida, Y., Kurosaka, Y., Otani, T., Sato, K., and Kobayashi, H. (1998) Antimicrob. Agents Chemother., 42, 1641–1645.PubMedGoogle Scholar
  10. 10.
    Hassett, D. J., Ma, J. F., Elkins, J. G., McDermott, T. R., Ochsner, U. A., West, S. E., Huang, C. T., Fredericks, J., Burnett, S., Stewart, P. S., McFeters, G., Passador, L., and Iglewski, B. H. (1999) Mol. Microbiol., 34, 1082–1093.PubMedGoogle Scholar
  11. 11.
    Elkins, J. G., Hassett, D. J., Stewart, P. S., Schweizer, H. P., and McDermott, T. R. (1999) Appl. Environ. Microbiol., 65, 4594–4600.PubMedGoogle Scholar
  12. 12.
    Anderl, J. N., Franklin, M. J., and Stewart, P. S. (2000) Antimicrob. Agents Chemother., 44, 1818–1824.PubMedGoogle Scholar
  13. 13.
    Stewart, P. S. (2003) J. Bacteriol., 185, 1485–1491.PubMedGoogle Scholar
  14. 14.
    Gilbert, P., Alison, D. G., Rickhard, A., Sufya, N., Whyte, F., and McBain, A. J. (2001) in Biofilm Community Development: Chance or Necessity? (Gilbert, P., Allison, D. G., Brading, M., Verran, J., and Walker, J., eds.) Bioline Press, Cardiff.Google Scholar
  15. 15.
    Gilbert, P., Das, J., and Foley, I. (1997) Adv. Dent. Res., 11, 160–167.CrossRefPubMedGoogle Scholar
  16. 16.
    Costerton, J. W., Stewart, P. S., and Greenberg, E. P. (1999) Science, 284, 1318–1322.PubMedGoogle Scholar
  17. 17.
    Brooun, A., Liu, S., and Lewis, K. (2000) Antimicrob. Agents Chemother., 44, 640–646.PubMedGoogle Scholar
  18. 18.
    Lewis, K. (2001) Antimicrob. Agents Chemother., 45, 999–1007.PubMedGoogle Scholar
  19. 19.
    Bigger, J. W. (1944) Lancet, 11, 497–500.Google Scholar
  20. 20.
    Keren, I., Kaldalu, N., Spoering, A., Wang, Y., and Lewis, K. (2004) FEMS Microbiol. Lett., 230, 13–18.PubMedGoogle Scholar
  21. 21.
    Spoering, A. L., and Lewis, K. (2001) J. Bacteriol., 183, 6746–6751.PubMedGoogle Scholar
  22. 22.
    Keren, I., Shah, D., Spoering, A., Kaldalu, N., and Lewis, K. (2005) J. Bacteriol., in press.Google Scholar
  23. 23.
    Leid, J. G., Shirtliff, M. E., Costerton, J. W., and Stoodley, A. P. (2002) Infect. Immun., 70, 6339–6345.PubMedGoogle Scholar
  24. 24.
    Jesaitis, A. J., Franklin, M. J., Berglund, D., Sasaki, M., Lord, C. I., Bleazard, J. B., Duffy, J. E., Beyenal, M., and Lewanowski, Z. (2003) J. Immunol., 171, 4329–4339.PubMedGoogle Scholar
  25. 25.
    Vuong, C., Voyich, J. M., Fischer, E. R., Braughton, K. R., Whitney, A. R., DeLeo, F. R., and Otto, M. (2004) Cell Microbiol., 6, 269–275.PubMedGoogle Scholar
  26. 26.
    Moyed, H. S., and Bertrand, K. P. (1983) J. Bacteriol., 155, 768–775.PubMedGoogle Scholar
  27. 27.
    Falla, T. J., and Chopra, I. (1998) Antimicrob. Agents Chemother., 42, 3282–3284.PubMedGoogle Scholar
  28. 28.
    Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., and Leibler, S. (2004) Science, 305, 1622–1625.PubMedGoogle Scholar
  29. 29.
    Lewis, K. (1998) J. Theor. Biol., 193, 359–363.PubMedGoogle Scholar
  30. 30.
    Tomasz, A., Albino, A., and Zanati, E. (1970) Nature, 227, 138–140.PubMedGoogle Scholar
  31. 31.
    Rice, K. C., and Bayles, K. W. (2003) Mol. Microbiol., 50, 729–738.PubMedGoogle Scholar
  32. 32.
    Selinger, D. W., Cheung, K. J., Mei, R., Johansson, E. M., Richmond, C. S., Blattner, F. R., Lockhart, D. J., and Church, G. M. (2000) Nat. Biotechnol., 18, 1262–1268.PubMedGoogle Scholar
  33. 33.
    Kaldalu, N., Mei, R., and Lewis, K. (2004) Antimicrob. Agents Chemother., 48, 890–896.PubMedGoogle Scholar
  34. 34.
    Wada, A. (1998) Genes Cells, 3, 203–208.PubMedGoogle Scholar
  35. 35.
    Opperman, T., Murli, S., Smith, B. T., and Walker, G. C. (1999) Proc. Natl. Acad. Sci. USA, 96, 9218–9223.PubMedGoogle Scholar
  36. 36.
    Walker, G. C. (1996) in Escherichia coli and Samonella. Cellular and Molecular Biology (Neidhardt, F. C., ed.) ASM Press, Washington, DC, pp. 1400–1416.Google Scholar
  37. 37.
    Brown, J. M., and Shaw, K. J. (2003) J. Bacteriol., 185, 6600–6608.PubMedGoogle Scholar
  38. 38.
    Hayes, F. (2003) Science, 301, 1496–1499.PubMedGoogle Scholar
  39. 39.
    Sat, B., Hazan, R., Fisher, T., Khaner, H., Glaser, G., and Engelberg-Kulka, H. (2001) J. Bacteriol., 183, 2041–2045.PubMedGoogle Scholar
  40. 40.
    Pedersen, K., Christensen, S. K., and Gerdes, K. (2002) Mol. Microbiol., 45, 501–510.PubMedGoogle Scholar
  41. 41.
    Christensen, S. K., Pedersen, K., Hansen, F. G., and Gerdes, K. (2003) J. Mol. Biol., 332, 809–819.PubMedGoogle Scholar
  42. 42.
    Pedersen, K., Zavialov, A. V., Pavlov, M. Y., Elf, J., Gerdes, K., and Ehrenberg, M. (2003) Cell, 112, 131–140.PubMedGoogle Scholar
  43. 43.
    Moyed, H. S., and Broderick, S. H. (1986) J. Bacteriol., 166, 399–403.PubMedGoogle Scholar
  44. 44.
    Black, D. S., Kelly, A. J., Mardis, M. J., and Moyed, H. S. (1991) J. Bacteriol., 173, 5732–5739.PubMedGoogle Scholar
  45. 45.
    Black, D. S., Irwin, B., and Moyed, H. S. (1994) J. Bacteriol., 176, 4081–4091.PubMedGoogle Scholar
  46. 46.
    Falla, T. J., and Chopra, I. (1999) Microbiology, 145, 515–516.PubMedCrossRefGoogle Scholar
  47. 47.
    Lewis, K. (2000) Microbiol. Mol. Biol. Rev., 64, 503–514.PubMedGoogle Scholar
  48. 48.
    Spudich, J. L., and Koshland, D. E., Jr. (1976) Nature, 262, 467–471.PubMedGoogle Scholar
  49. 49.
    Korobkova, E., Emonet, T., Vilar, J. M., Shimizu, T. S., and Cluzel, P. (2004) Nature, 428, 574–578.PubMedGoogle Scholar
  50. 50.
    Mah, T. F., Pitts, B., Pellock, B., Walker, G. C., Stewart, P. S., and O’Toole, G. A. (2003) Nature, 426, 306–310.PubMedGoogle Scholar
  51. 51.
    Drenkard, E., and Ausubel, F. M. (2002) Nature, 416, 740–743.PubMedGoogle Scholar
  52. 52.
    Mukamolova, G. V., Turapov, O. A., Young, D. I., Kaprelyants, A. S., Kell, D. B., and Young, M. (2002) Mol. Microbiol., 46, 623–635.PubMedGoogle Scholar
  53. 53.
    Tufariello, J. M., Chan, J., and Flynn, J. L. (2003) Lancet Infect. Dis., 3, 578–590.PubMedGoogle Scholar
  54. 54.
    Colwell, R. R., and Grimes, D. J. (2000) Nonculturable Microorganisms in the Environment, American Society for Microbiology, Washington, DC.Google Scholar
  55. 55.
    Bogosian, G., and Bourneuf, E. V. (2001) EMBO Rep., 2, 770–774.PubMedGoogle Scholar
  56. 56.
    Kaeberlein, T., Lewis, K., and Epstein, S. S. (2002) Science, 296, 1127–1129.PubMedGoogle Scholar
  57. 57.
    Skulachev, V. P. (2002) Ann. N. Y. Acad. Sci., 959, 214–237.PubMedCrossRefGoogle Scholar
  58. 58.
    Hazan, R., Sat, B., and Engelberg-Kulka, H. (2004) J. Bacteriol., 186, 3663–3669.PubMedGoogle Scholar

Copyright information

© MAIK “Nauka/Interperiodica” 2005

Authors and Affiliations

  • K. Lewis
    • 1
  1. 1.Northeastern UniversityBostonUSA

Personalised recommendations