Distinguishing between resistance, tolerance and persistence to antibiotic treatment

Nature Reviews Microbiology

Volumn 14, Issue 5, 2016, Pages 320-330

  Brauner, Asher ^a   Fridman, Ofer ^a   Gefen, Orit ^a   Balaban, Nathalie Q ^a  

^a HEBREW UNIVERSITY OF JERUSALEM   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; BACTERIAL ENZYME; ANTIINFECTIVE AGENT;

ANTIBIOTIC RESISTANCE; ANTIBIOTIC THERAPY; BACTERIAL GENE; BACTERIAL STRAIN; DRUG TOLERANCE; ENZYME ACTIVITY; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REVIEW; BACTERIUM; DRUG EFFECTS; GENETICS; GROWTH, DEVELOPMENT AND AGING; MICROBIAL SENSITIVITY TEST;

ANTI-BACTERIAL AGENTS; BACTERIA; DRUG RESISTANCE, BACTERIAL; DRUG TOLERANCE; MICROBIAL SENSITIVITY TESTS;

EID: 84964318468     PISSN: 17401526     EISSN: 17401534     Source Type: Journal    
DOI: 10.1038/nrmicro.2016.34     Document Type: Review

References (116)

1. McKeegan, K. S., Borges-Walmsley, M. I., & Walmsley, A. R. Microbial and viral drug resistance mechanisms. Trends Microbiol. 10, S8-S14 (2002
2. Scholar, E M., & Pratt, W. B. (eds) The Antimicrobial Drugs (Oxford Univ. Press 2000
3. D?Costa, V. M., McGrann, K. M., Hughes, D. W., & Wright, G. D. Sampling the antibiotic resistome. Science 311, 374-377 (2006
4. Bigger, J. W. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244, 497-500 (1944
5. Hobby, G. L., Meyer, K., & Chaffee, E. Observations on the mechanism of action of penicillin. Proc. Soc. Exp. Biol. Med. 50, 281-285 (1942
6. Horne, D., & Tomasz, A. Tolerant response of Streptococcus sanguis to β-lactams and other cell-wall inhibitors. Antimicrob. Agents Chemother. 11, 888-896 (1977
7. Balaban, N. Q., Gerdes, K., Lewis, K., & McKinney, J. D. A problem of persistence: still more questions than answers?. Nat. Rev. Microbiol. 11, 587-591 (2013
8. Kester, J. C., & Fortune, S. M. Persisters and beyond: mechanisms of phenotypic drug resistance and drug tolerance in bacteria. Crit. Rev. Biochem. Mol. Biol. 49, 91-101 (2014
9. Handwerger, S., & Tomasz, A. Antibiotic tolerance among clinical isolates of bacteria. Annu. Rev. Pharmacol. Toxicol. 25, 349-380 (1985
10. Tuomanen, E., Cozens, R., Tosch, W., Zak, O., & Tomasz, A. The rate of killing of Escherichia coli by β-lactam antibiotics is strictly proportional to the rate of bacterial growth. J. Gen. Microbiol. 132, 1297-1304 (1986
11. McDermott, W. Microbial persistence. Yale J. Biol. Med. 30, 257-291 (1958
12. Lederberg, J., & Zinder, N. Concentration of biochemical mutants of bacteria with penicillin. J. Am. Chem. Soc. 70, 4267-4268 (1948
13. Gefen, O., & Balaban, N. Q. The importance of being persistent: heterogeneity of bacterial populations under antibiotic stress. FEMS Microbiol. Rev. 33, 704-717 (2009
14. Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., & Leibler, S. Bacterial persistence as a phenotypic switch. Science 305, 1622-1625 (2004
15. Wakamoto Y., et al. Dynamic persistence of antibiotic-stressed mycobacteria. Science 339, 91-95 (2013
16. Depardieu, F., Podglajen, I., Leclercq, R., Collatz, E., & Courvalin, P. Modes and modulations of antibiotic resistance gene expression. Clin. Microbiol. Rev. 20, 79-114 (2007
17. Blair, J. M., Webber, M. A., Baylay, A. J., Ogbolu, D. O., & Piddock, L. J. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 13, 42-51 (2015
18. Chait, R., Craney, A., & Kishony, R. Antibiotic interactions that select against resistance. Nature 446, 668-671 (2007
19. Wiegand, I., Hilpert, K., & Hancock, R. E. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat. Protoc. 3, 163-175 (2008
20. Mattie, H. Antibiotic efficacy in vivo predicted by in vitro activity. Int. J. Antimicrob. Agents 14, 91-98 (2000
21. Paterson D. L., et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum β-lactamases: implications for the clinical microbiology laboratory. J. Clin. Microbiol. 39, 2206-2212 (2001
22. Ishida, K., Guze, P. A., Kalmanson, G. M., Albrandt, K., & Guze, L. B. Variables in demonstrating methicillin tolerance in Staphylococcus aureus strains. Antimicrob. Agents Chemother. 21, 688-690 (1982
23. Wolfson, J., Hooper, D., McHugh, G., Bozza, M., & Swartz, M. Mutants of Escherichia coli K-12 exhibiting reduced killing by both quinolone and β-lactam antimicrobial agents. Antimicrob. Agents Chemother. 34, 1938-1943 (1990
24. Mueller, M., de la Pena, A., & Derendorf, H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. Antimicrob. Agents Chemother. 48, 369-377 (2004
25. Barry L. A. et al. Methods for determining bactericidal activity of antimicrobial agents; approved guideline. (National Committee for Clinical Laboratory Standards, 1999
26. Keren, I., Kaldalu, N., Spoering, A., Wang, Y. P., & Lewis, K. Persister cells and tolerance to antimicrobials. Fems Microbiol. Lett. 230, 13-18 (2004
27. Pasticci M. B., et al. Bactericidal activity of oxacillin and glycopeptides against Staphylococcus aureus in patients with endocarditis: looking for a relationship between tolerance and outcome. Ann. Clin. Microbiol. Antimicrob. 10, 26 (2011
28. Fridman, O., Goldberg, A., Ronin, I., Shoresh, N., & Balaban, N. Q. Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations. Nature 513, 418-421 (2014
29. Regoes R. R., et al. Pharmacodynamic functions: a multiparameter approach to the design of antibiotic treatment regimens. Antimicrob. Agents Chemother. 48, 3670-3676 (2004
30. Gefen, O., Gabay, C., Mumcuoglu, M., Engel, G., & Balaban, N. Q. Single-cell protein induction dynamics reveals a period of vulnerability to antibiotics in persister bacteria. Proc. Natl Acad. Sci. USA 105, 6145-6149 (2008
31. Helaine S., et al. Dynamics of intracellular bacterial replication at the single cell level. Proc. Natl Acad. Sci. USA 107, 3746-3751 (2010
32. Amato, S. M., Orman, M. A., & Brynildsen, M. P. Metabolic control of persister formation in Escherichia coli. Mol. Cell 50, 475-487 (2013
33. Maisonneuve, E., Castro-Camargo, M., & Gerdes, K (p)ppGpp controls bacterial persistence by stochastic induction of toxin-Antitoxin activity. Cell 154 1140-1150 2013
34. Chao, L., & Levin, B. R. Structured habitats and the evolution of anticompetitor toxins in bacteria. Proc. Natl Acad. Sci. USA 78, 6324-6328 (1981
35. Rodionov, D. G., & Ishiguro, E. E. Effects of inhibitors of protein synthesis on lysis of Escherichia coli induced by β-lactam antibiotics. Antimicrob. Agents Chemother. 40, 899-903 (1996
36. Orman, M. A., & Brynildsen, M. P. Dormancy is not necessary or sufficient for bacterial persistence. Antimicrob. Agents Chemother. 57, 3230-3239 (2013
37. Johansen, H. K., Jensen, T. G., Dessau, R. B., Lundgren, B., & Frimodt-Moller, N. Antagonism between penicillin and erythromycin against Streptococcus pneumoniae in vitro and in vivo. J. Antimicrob. Chemother. 46, 973-980 (2000
38. Thonus, I. P., Fontijne, P., & Michel, M. F. Ampicillin susceptibility and ampicillin-induced killing rate of Escherichia coli. Antimicrob. Agents Chemother. 22, 386-390 (1982
39. Mascio, C. T., Alder, J. D., & Silverman, J. A. Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells. Antimicrob. Agents Chemother. 51, 4255-4260 (2007
40. de Steenwinkel, J. E., et al. Time-kill kinetics of anti-Tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis. J. Antimicrob. Chemother. 65, 2582-2589 (2010
41. Evans, D. J., Allison, D. G., Brown, M. R., & Gilbert, P. Susceptibility of Pseudomonas aeruginosa and Escherichia coli biofilms towards ciproflaxin: effect of specific growth rate. J. Antimicrob. Chemother. 27, 177-184 (1991
42. Manina, G., Dhar, N., & McKinney, J. D. Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell Host Microbe 17, 32-46 (2015
43. Kitano, K., & Tomasz, A. Escherichia coli mutants tolerant to β-lactam antibiotics. J. Bacteriol. 140, 955-963 (1979
44. Bernier, S. P., et al. Starvation, together with the SOS response, mediates high biofilm-specific tolerance to the fluoroquinolone ofloxacin. PloS Genet. 9, e1003144 (2013
45. Sandberg A., et al. Intra-And extracellular activities of dicloxacillin against Staphylococcus aureus in vivo and in vitro. Antimicrob. Agents Chemother. 54, 2391-2400 (2010
46. Dorr, T., Davis, B. M., & Waldor, M. K. Endopeptidase-mediated β-lactam tolerance. PloS Pathog. 11, e1004850 (2015
47. Dorr, T., Vulic, M., & Lewis, K. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PloS Biol. 8, e1000317 (2010
48. Wiuff, C., & Andersson, D. I. Antibiotic treatment in vitro of phenotypically tolerant bacterial populations. J. Antimicrob. Chemother. 59, 254-263 (2007
49. Johnson, P. J. T., & Levin, B. R. Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus. PloS Genet. 9, e1003123 (2013
50. Gefen, O., Fridman, O., Ronin, I., & Balaban, N. Q. Direct observation of single stationary-phase bacteria reveals a surprisingly long period of constant protein production activity. Proc. Natl Acad. Sci. USA 111, 556-561 (2014
51. Lewis, K. Persister cells, dormancy and infectious disease. Nat. Rev. Microbiol. 5, 48-56 (2007
52. Nguyen D., et al. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 334, 982-986 (2011
53. Levin-Reisman I., et al. Automated imaging with ScanLag reveals previously undetectable bacterial growth phenotypes. Nat. Methods 7, 737-739 (2010
54. Luidalepp, H., Joers, A., Kaldalu, N., & Tenson, T. Age of inoculum strongly influences persister frequency and can mask effects of mutations implicated in altered persistence. J. Bacteriol. 193, 3598-3605 (2011
55. Madar D., et al. Promoter activity dynamics in the lag phase of Escherichia coli. BMC Syst. Biol. 7, 136 (2013
56. Joers, A., Kaldalu, N., & Tenson, T. The frequency of persisters in Escherichia coli reflects the kinetics of awakening from dormancy. J. Bacteriol. 192, 3379-3384 (2010
57. Putrinš, M., Kogermann, K., Lukk, E., & Lippus, M. Phenotypic heterogeneity enables uropathogenic Escherichia coli to evade killing by antibiotics and serum complement. Infect. Immun. 83, 1056-1067 (2015
58. Pearl, S., Gabay, C., Kishony, R., Oppenheim, A., & Balaban, N. Q. Nongenetic individuality in the host-phage interaction. PloS Biol. 6, 957-964 (2008
59. Baranyi, J. Stochastic modelling of bacterial lag phase. Int. J. Food Microbiol. 73, 203-206 (2002
60. Akerlund, T., Nordstrom, K., & Bernander, R. Analysis of cell size and DNA content in exponentially growing and stationary-phase batch cultures of Escherichia coli. J. Bacteriol. 177, 6791-6797 (1995
61. Hartman, B. J., & Tomasz, A. Expression of methicillin resistance in heterogeneous strains of Staphylococcus aureus. Antimicrob. Agents Chemother. 29, 85-92 (1986
62. Levin, B. R., & Rozen, D. E. Non-inherited antibiotic resistance. Nat. Rev. Microbiol. 4, 556-562 (2006
63. Nataro, J. P., Blaser, M. J., & Cunningham-Rundles, S. (eds) in Persistent Bacterial Infections. 3-10 (ASM Press, 2000
64. Rotem E., et al. Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Proc. Natl Acad. Sci. USA 107, 12541-12546 (2010
65. Korch, S. B., & Hill, T. M. Ectopic overexpression of wild-Type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation. J. Bacteriol. 188, 3826-3836 (2006
66. Moyed, H. S., & Bertrand, K. P. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 155, 768-775 (1983
67. Levin-Reisman, I., & Balaban, N Q. in Bacterial Persistence: Methods and Protocols (eds Michiels, J., & Fauvart, M.) 75-81 (Humana Press 2015
68. El Meouche, I., Siu, Y., & Dunlop, M. J. Stochastic expression of a multiple antibiotic resistance activator confers transient resistance in single cells. Sci. Rep. 6, 19538 (2016
69. Adams K. N., et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145, 39-53 (2011
70. Kayser, F. H., Benner, E. J., & Hoeprich, P. D. Acquired and native resistance of Staphylococcus aureus to cephalexin and other β lactam antibiotics. Appl. Microbiol. 20, 1-5 (1970
71. El Halfawy, O. M., & Valvano, M. A. Antimicrobial heteroresistance: an emerging field in need of clarity. Clin. Microbiol. Rev. 28, 191-207 (2015
72. Adams, K. N., Szumowski, J. D., & Ramakrishnan, L. Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-Tubercular drugs. J. Infect. Dis. 210, 456-466 (2014
73. Mattie, H., Sekh, B. A., van Ogtrop, M. L., & van Strijen, E. Comparison of the antibacterial effects of cefepime and ceftazidime against Escherichia coli in vitro and in vivo. Antimicrob. Agents Chemother. 36, 2439-2443 (1992
74. Coates, A. R., & Hu, Y. Targeting non-multiplying organisms as a way to develop novel antimicrobials. Trends Pharmacol. Sci. 29, 143-150 (2008
75. Feng J., et al. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library. Emerg. Microbes Infect. 3, e49 (2014
76. Kim J. S., et al. Selective killing of bacterial persisters by a single chemical compound without affecting normal antibiotic-sensitive cells. Antimicrob. Agents Chemother. 55, 5380-5383 (2011
77. Fleck L. E., et al. A screen for and validation of prodrug antimicrobials. Antimicrob. Agents Chemother. 58, 1410-1419 (2014
78. Conlon B. P., et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365-370 (2013
79. Roostalu, J., Jõers, A., Luidalepp, H., Kaldalu, N., & Tenson, T. Cell division in Escherichia coli cultures monitored at single cell resolution. BMC Microbiol. 8, 68 (2008
80. Claudi B., et al. Phenotypic variation of Salmonella in host tissues delays eradication by antimicrobial chemotherapy. Cell 158, 722-733 (2014
81. Mattie, H., Zhang, L. C., van Strijen, E., Sekh, B. R., & Douwes-Idema, A. E. Pharmacokinetic and pharmacodynamic models of the antistaphylococcal effects of meropenem and cloxacillin in vitro and in experimental infection. Antimicrob. Agents Chemother. 41, 2083-2088 (1997
82. Arnoldini M., et al. Bistable expression of virulence genes in Salmonella leads to the formation of an antibiotic-Tolerant subpopulation. PLoS Biol. 12, e1001928 (2014
83. Nickel, J. C., Ruseska, I., Wright, J. B., & Costerton, J. W. Tobramycin resistance of Pseudomonas aeruginosa cells growing as a biofilm on urinary catheter material. Antimicrob. Agents Chemother. 27, 619-624 (1985
84. Hayes, C. S., & Low, D. A. Signals of growth regulation in bacteria. Curr. Opin. Microbiol. 12, 667-673 (2009
85. Bhuyan, B. K., Fraser, T. J., & Day, K. J. Cell proliferation kinetics and drug sensitivity of exponential and stationary populations of cultured L1210 cells. Cancer Res. 37, 1057-1063 (1977
86. Sharma, S V., et al. A chromatin-mediated reversible drug-Tolerant state in cancer cell subpopulations. Cell 141 69-80 2010
87. Jayaraman, R. Bacterial persistence: some new insights into an old phenomenon. J. Biosci. 33, 795-805 (2008
88. Cohen, N. R., Lobritz, M. A., & Collins, J. J. Microbial persistence and the road to drug resistance. Cell Host Microbe 13, 632-642 (2013
89. Potrykus, K., & Cashel, M. (p)ppGpp: still magical?. Annu. Rev. Microbiol. 62, 35-51 (2008
90. Kaspy I., et al. HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-TRNA-synthetase. Nat. Commun. 4, 3001 (2013
91. Germain, E., Castro-Roa, D., Zenkin, N., & Gerdes, K. Molecular mechanism of bacterial persistence by HipA. Mol. Cell 52, 248-254 (2013
92. Hahn, J., Tanner, A. W., Carabetta, V. J., Cristea, I. M., & Dubnau, D. ComGA-RelA interaction and persistence in the Bacillus subtilis K-state. Mol. Microbiol. 97, 454-471 (2015
93. Gerdes, K., & Maisonneuve, E. Bacterial persistence and toxin-Antitoxin loci. Annu. Rev. Microbiol. 66, 103-123 (2012
94. Girgis, H. S., Harris, K., & Tavazoie, S. Large mutational target size for rapid emergence of bacterial persistence. Proc. Natl Acad. Sci. USA 109, 12740-12745 (2012
95. Hansen, S., Lewis, K., & Vulic, M. Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrob. Agents Chemother. 52, 2718-2726 (2008
96. Spoering, A. L., Vulic, M., & Lewis, K. GlpD and PlsB participate in persister cell formation in Escherichia coli. J. Bacteriol. 188, 5136-5144 (2006
97. Vazquez-Laslop, N., Lee, H., & Neyfakh, A. A. Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. J. Bacteriol. 188, 3494-3497 (2006
98. Shan, Y., Lazinski, D., Rowe, S. E., Camili, A., & Lewis, K. Genetic basis of persister tolerance to aminoglycosides in Escherichia coli. mBio 6, e00078 15 (2015
99. Balaban, N. Q. Persistence: mechanisms for triggering and enhancing phenotypic variability. Curr. Opin. Genet. Dev. 21, 768-775 (2011
100. Casadesus, J., & Low, D. A. Programmed heterogeneity: epigenetic mechanisms in bacteria. J. Biol. Chem. 288, 13929-13935 (2013
101. Huh, D., & Paulsson, J. Non-genetic heterogeneity from stochastic partitioning at cell division. Nat. Genet. 43, 95-100 (2011
102. Tsimring, L. S. Noise in biology. Rep. Progress Phys. 77, 026601 (2014
103. Gelens, L., Hill, L., Vandervelde, A., Danckaert, J., & Loris, R. A general model for toxin-Antitoxin module dynamics can explain persister cell formation in E. coli. PLoS Comput. Biol. 9, e1003190 (2013
104. Maisonneuve, E., Shakespeare, L. J., Jorgensen, M. G., & Gerdes, K. Bacterial persistence by RNA endonucleases. Proc. Natl Acad. Sci. USA 108, 13206-13211 (2011
105. Helaine S., et al. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343, 204-208 (2014
106. Aldridge B. B., et al. Asymmetry and aging of mycobacterial cells lead to variable growth and antibiotic susceptibility. Science 335, 100-104 (2012
107. Kieser, K. J., & Rubin, E. J. How sisters grow apart: mycobacterial growth and division. Nat. Rev. Microbiol. 12, 550-562 (2014
108. Vaubourgeix J., et al. Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells. Cell Host Microbe 17, 178-190 (2015
109. Wu, Y. X., Vulic, M., Keren, I., & Lewis, K. Role of oxidative stress in persister tolerance. Antimicrob. Agents Chemother. 56, 4922-4926 (2012
110. Song, Y., Rubio, A., Jayaswal, R. K., Silverman, J. A., & Wilkinson, B. J. Additional routes to Staphylococcus aureus daptomycin resistance as revealed by comparative genome sequencing, transcriptional profiling, and phenotypic studies. PLoS ONE 8, e58469 (2013
111. Brehm-Stecher, B. F., & Johnson, E. A. Single-cell microbiology: tools, technologies, and applications. Microbiol. Mol. Biol. Rev. 68, 538-559 (2004
112. Ping W., et al. Robust growth of Escherichia coli. Curr. Biol. 20, 1099-1103 (2010
113. Iino, R., Matsumoto, Y., Nishino, K., Yamaguchi, A., & Noji, H. Design of a large-scale femtoliter droplet array for single-cell analysis of drug-Tolerant and drug-resistant bacteria. Front. Microbiol. 4, 300 (2013
114. Shah D., et al. Persisters: a distinct physiological state of E. coli. BMC Microbiol. 6, 53 (2006
115. Orman, M. A., & Brynildsen, M. P. Establishment of a method to rapidly assay bacterial persister metabolism. Antimicrob. Agents Chemother. 57, 4398-4409 (2013
116. Jarzembowski, T., Wisniewska, K., Jozwik, A., & Witkowski, J. Heterogeneity of methicillin-resistant Staphylococcus aureus strains (MRSA) characterized by flow cytometry. Curr. Microbiol. 59, 78-80 (2009