Mechanisms of bacterial persistence during stress and antibiotic exposure

Science

Volumn 354, Issue 6318, 2016, Pages

  Harms, Alexander ^a   Maisonneuve, Etienne ^a   Gerdes, Kenn ^a  

^a Center of Excellence for Bacterial Stress Response and Persistence (BASP)   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; ENDONUCLEASE; ENDOPEPTIDASE LA; GUANOSINE TRIPHOSPHATASE; MESSENGER RNA; ANTIINFECTIVE AGENT; BACTERIAL PROTEIN; BACTERIAL TOXIN; GUANOSINE 3' DIPHOSPHATE 5' TRIPHOSPHATE; SIGMA FACTOR; SIGMA FACTOR KATF PROTEIN, BACTERIA;

ANTIMICROBIAL ACTIVITY; BACTERIUM; DRUG RESISTANCE; HETEROGENEITY; PERSISTENCE; PHYSIOLOGICAL RESPONSE; TOLERANCE; TOXIN;

ANTIBIOTIC RESISTANCE; ANTIBIOTIC THERAPY; ARTICLE; BIOFILM; DNA DAMAGE RESPONSE; DRUG EXPOSURE; ENERGY METABOLISM; ESCHERICHIA COLI K 12; MICROBIAL COMMUNITY; NONHUMAN; PERSISTENT INFECTION; PHENOTYPE; PRIORITY JOURNAL; SECOND MESSENGER; SIGNAL TRANSDUCTION; STRESS; ADAPTATION; ANTAGONISTS AND INHIBITORS; BACTERIAL INFECTIONS; BACTERIUM; DNA DAMAGE; DRUG EFFECTS; GENETICS; MARKOV CHAIN; METABOLISM; MICROBIOLOGY; MULTIDRUG RESISTANCE; PHYSIOLOGICAL STRESS; PHYSIOLOGY; PROTON MOTIVE FORCE; SOS RESPONSE (GENETICS);

BACTERIA (MICROORGANISMS);

ADAPTATION, PHYSIOLOGICAL; ANTI-BACTERIAL AGENTS; BACTERIA; BACTERIAL INFECTIONS; BACTERIAL PROTEINS; BACTERIAL TOXINS; BIOFILMS; DNA DAMAGE; DRUG RESISTANCE, MULTIPLE, BACTERIAL; GUANOSINE PENTAPHOSPHATE; PROTON-MOTIVE FORCE; SIGMA FACTOR; SIGNAL TRANSDUCTION; SOS RESPONSE (GENETICS); STOCHASTIC PROCESSES; STRESS, PHYSIOLOGICAL;

EID: 85006247350     PISSN: 00368075     EISSN: 10959203     Source Type: Journal    
DOI: 10.1126/science.aaf4268     Document Type: Article

References (134)

1. World Health Organization (WHO), "Antimicrobial resistance: Global report on surveillance 2014 (WHO, 2014); www.who.int/drugresistance/documents/surveillancereport/en/.
2. M. Fauvart, V. N. De Groote, J. Michiels, Role of persister cells in chronic infections: Clinical relevance and perspectives on anti-persister therapies. J. Med. Microbiol. 60, 699-709 (2011). doi: 10.1099/jmm.0.030932-0; pmid: 21459912
3. N. Q. Balaban, K. Gerdes, K. Lewis, J. D. McKinney, A problem of persistence: Still more questions than answers? Nat. Rev. Microbiol. 11, 587-591 (2013). doi: 10.1038/ nrmicro3076; pmid: 24020075
4. B. R. Levin, D. E. Rozen, Non-inherited antibiotic resistance. Nat. Rev. Microbiol. 4, 556-562 (2006). doi: 10.1038/ nrmicro1445; pmid: 16778840
5. K. Lewis, Persister cells. Annu. Rev. Microbiol. 64, 357-372 (2010). doi: 10.1146/annurev.micro.112408.134306; pmid: 20528688
6. N. Q. Balaban, J. Merrin, R. Chait, L. Kowalik, S. Leibler, Bacterial persistence as a phenotypic switch. Science 305, 1622-1625 (2004). doi: 10.1126/science.1099390; pmid: 15308767
7. E. Maisonneuve, K. Gerdes, Molecular mechanisms underlying bacterial persisters. Cell 157, 539-548 (2014). doi: 10.1016/j.cell.2014.02.050; pmid: 24766804
8. T. K. Wood, Combatting bacterial persister cells. Biotechnol. Bioeng. 113, 476-483 (2016). doi: 10.1002/bit.25721; pmid: 26264116
9. D. M. Livermore, Has the era of untreatable infections arrived? J. Antimicrob. Chemother. 64 (suppl. 1), i29-i36 (2009). doi: 10.1093/jac/dkp255; pmid: 19675016
10. T. Bjarnsholt, The role of bacterial biofilms in chronic infections. APMIS Suppl. 121, 1-51 (2013). doi: 10.1111/ apm.12099; pmid: 23635385
11. D. Lebeaux, J. M. Ghigo, C. Beloin, Biofilm-related infections: Bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol. Mol. Biol. Rev. 78, 510-543 (2014). doi: 10.1128/ MMBR.00013-14; pmid: 25184564
12. M. G. Blango, M. A. Mulvey, Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrob. Agents Chemother. 54, 1855-1863 (2010). doi: 10.1128/ AAC.00014-10; pmid: 20231390
13. K. N. Adams et al., Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145, 39-53 (2011). doi: 10.1016/j.cell.2011.02.022; pmid: 21376383
14. B. Claudi et al., Phenotypic variation of Salmonella in host tissues delays eradication by antimicrobial chemotherapy. Cell 158, 722-733 (2014). doi: 10.1016/j.cell.2014.06.045; pmid: 25126781
15. S. Helaine et al., Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343, 204-208 (2014). doi: 10.1126/science.1244705; pmid: 24408438
16. G. Manina, N. Dhar, J. D. McKinney, Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell Host Microbe 17, 32-46 (2015). doi: 10.1016/ j.chom.2014.11.016; pmid: 25543231
17. P. Kaiser et al., Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment. PLOS Biol. 12, e1001793 (2014). doi: 10.1371/ journal.pbio.1001793; pmid: 24558351
18. M. A. Schumacher et al., HipBA-promoter structures reveal the basis of heritable multidrug tolerance. Nature 524, 59-64 (2015). doi: 10.1038/nature14662; pmid: 26222023
19. J. E. Michiels, B. Van den Bergh, N. Verstraeten, M. Fauvart, J. Michiels, In vitro emergence of high persistence upon periodic aminoglycoside challenge in the ESKAPE pathogens. Antimicrob. Agents Chemother. 60, 4630-4637 (2016). doi: 10.1128/AAC.00757-16; pmid: 27185802
20. H. S. Moyed, K. P. Bertrand, 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). pmid: 6348026
21. H. L. Torrey, I. Keren, L. E. Via, J. S. Lee, K. Lewis, High persister mutants in Mycobacterium tuberculosis. PLOS ONE 11, e0155127 (2016). doi: 10.1371/journal.pone.0155127; pmid: 27176494
22. B. Van den Bergh et al., Frequency of antibiotic application drives rapid evolutionary adaptation of Escherichia coli persistence. Nat. Microbiol. 1, 16020 (2016). doi: 10.1038/ nmicrobiol.2016.20; pmid: 27572640
23. K. Stepanyan et al., Fitness trade-offs explain low levels of persister cells in the opportunistic pathogen Pseudomonas aeruginosa. Mol. Ecol. 24, 1572-1583 (2015). doi: 10.1111/mec.13127; pmid: 25721227
24. A. Slattery, A. H. Victorsen, A. Brown, K. Hillman, G. J. Phillips, Isolation of highly persistent mutants of Salmonella enterica serovar Typhimurium reveals a new toxin-antitoxin module. J. Bacteriol. 195, 647-657 (2013). doi: 10.1128/JB.01397-12; pmid: 23204462
25. L. R. Mulcahy, J. L. Burns, S. Lory, K. Lewis, Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis. J. Bacteriol. 192, 6191-6199 (2010). doi: 10.1128/JB.01651-09; pmid: 20935098
26. L. W. Goneau et al., Selective target inactivation rather than global metabolic dormancy causes antibiotic tolerance in uropathogens. Antimicrob. Agents Chemother. 58, 2089-2097 (2014). doi: 10.1128/AAC.02552-13; pmid: 24449771
27. A. A. Al Mamun et al., Identity and function of a large gene network underlying mutagenic repair of DNA breaks. Science 338, 1344-1348 (2012). doi: 10.1126/science.1226683; pmid: 23224554
28. N. R. Cohen, M. A. Lobritz, J. J. Collins, Microbial persistence and the road to drug resistance. Cell Host Microbe 13, 632-642 (2013). doi: 10.1016/j.chom.2013.05.009; pmid: 23768488
29. M. A. Kohanski, D. J. Dwyer, J. J. Collins, How antibiotics kill bacteria: From targets to networks. Nat. Rev. Microbiol. 8, 423-435 (2010). doi: 10.1038/nrmicro2333; pmid: 20440275
30. J. Bigger, Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244, 497-500 (1944). doi: 10.1016/S0140-6736(00)74210-3
31. J. T. Lennon, S. E. Jones, Microbial seed banks: The ecological and evolutionary implications of dormancy. Nat. Rev. Microbiol. 9, 119-130 (2011). doi: 10.1038/ nrmicro2504; pmid: 21233850
32. O. Gefen, N. Q. Balaban, The importance of being persistent: Heterogeneity of bacterial populations under antibiotic stress. FEMS Microbiol. Rev. 33, 704-717 (2009). doi: 10.1111/j.1574-6976.2008.00156.x; pmid: 19207742
33. D. K. Fung, E. W. Chan, M. L. Chin, R. C. Chan, Delineation of a bacterial starvation stress response network which can mediate antibiotic tolerance development. Antimicrob. Agents Chemother. 54, 1082-1093 (2010). doi: 10.1128/AAC.01218-09; pmid: 20086164
34. E. Germain, M. Roghanian, K. Gerdes, E. Maisonneuve, 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 (2015). doi: 10.1073/ pnas.1423536112; pmid: 25848049
35. M. A. Orman, M. P. Brynildsen, Dormancy is not necessary or sufficient for bacterial persistence. Antimicrob. Agents Chemother. 57, 3230-3239 (2013). doi: 10.1128/AAC.00243-13; pmid: 23629720
36. K. Lewis, Persister cells and the riddle of biofilm survival. Biochemistry (Moscow) 70, 267-274 (2005). doi: 10.1007/ s10541-005-0111-6; pmid: 15807669
37. Y. Wakamoto et al., Dynamic persistence of antibioticstressed mycobacteria. Science 339, 91-95 (2013). doi: 10.1126/science.1229858; pmid: 23288538
38. S. M. Amato, M. P. Brynildsen, Persister heterogeneity arising from a single metabolic stress. Curr. Biol. 25, 2090-2098 (2015). doi: 10.1016/j.cub.2015.06.034; pmid: 26255847
39. E. Maisonneuve, L. J. Shakespeare, M. G. Jørgensen, K. Gerdes, Bacterial persistence by RNA endonucleases. Proc. Natl. Acad. Sci. U.S.A. 108, 13206-13211 (2011). doi: 10.1073/pnas.1100186108; pmid: 21788497
40. N. Verstraeten et al., Obg and membrane depolarization are part of a microbial bet-hedging strategy that leads to antibiotic tolerance. Mol. Cell 59, 9-21 (2015). doi: 10.1016/ j.molcel.2015.05.011; pmid: 26051177
41. T. Dörr, M. Vulić, K. Lewis, Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLOS Biol. 8, e1000317 (2010). doi: 10.1371/journal.pbio.1000317; pmid: 20186264
42. Y. Kim, T. K. Wood, 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 (2010). doi: 10.1016/j.bbrc.2009.11.033; pmid: 19909729
43. B. R. Levin, J. Concepción-Acevedo, K. I. Udekwu, Persistence: A copacetic and parsimonious hypothesis for the existence of non-inherited resistance to antibiotics. Curr. Opin. Microbiol. 21, 18-21 (2014). doi: 10.1016/ j.mib.2014.06.016; pmid: 25090240
44. O. Fridman, A. Goldberg, I. Ronin, N. Shoresh, N. Q. Balaban, Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations. Nature 513, 418-421 (2014). doi: 10.1038/nature13469; pmid: 25043002
45. B. Stewart, D. E. Rozen, Genetic variation for antibiotic persistence in Escherichia coli. Evolution 66, 933-939 (2012). doi: 10.1111/j.1558-5646.2011.01467.x; pmid: 22380453
46. N. Hofsteenge, E. van Nimwegen, O. K. Silander, Quantitative analysis of persister fractions suggests different mechanisms of formation among environmental isolates of E. coli. BMC Microbiol. 13, 25 (2013). doi: 10.1186/1471-2180-13-25; pmid: 23379956
47. T. Vogwill, A. C. Comfort, V. Furió, R. C. MacLean, Persistence and resistance as complementary bacterial adaptations to antibiotics. J. Evol. Biol. 29, 1223-1233 (2016). doi: 10.1111/ jeb.12864; pmid: 26999656
48. M. Arnoldini, R. Mostowy, S. Bonhoeffer, M. Ackermann, Evolution of stress response in the face of unreliable environmental signals. PLOS Comput. Biol. 8, e1002627 (2012). doi: 10.1371/journal.pcbi.1002627; pmid: 22916000
49. I. G. de Jong, P. Haccou, O. P. Kuipers, Bet hedging or not? A guide to proper classification of microbial survival strategies. BioEssays 33, 215-223 (2011). doi: 10.1002/bies.201000127; pmid: 21254151
50. E. Kussell, R. Kishony, N. Q. Balaban, S. Leibler, Bacterial persistence: A model of survival in changing environments. Genetics 169, 1807-1814 (2005). doi: 10.1534/ genetics.104.035352; pmid: 15687275
51. E. Maisonneuve, M. Castro-Camargo, K. Gerdes, (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity. Cell 154, 1140-1150 (2013). doi: 10.1016/j.cell.2013.07.048; pmid: 23993101
52. D. Shah et al., Persisters: A distinct physiological state of E. coli. BMC Microbiol. 6, 53 (2006). doi: 10.1186/1471-2180- 6-53; pmid: 16768798
53. O. Kotte, B. Volkmer, J. L. Radzikowski, M. Heinemann, Phenotypic bistability in Escherichia coli's central carbon metabolism. Mol. Syst. Biol. 10, 736 (2014). doi: 10.15252/ msb.20135022; pmid: 24987115
54. Y. Wu, M. Vulić, I. Keren, K. Lewis, Role of oxidative stress in persister tolerance. Antimicrob. Agents Chemother. 56, 4922-4926 (2012). doi: 10.1128/AAC.00921-12; pmid: 22777047
55. S. H. Hong, X. Wang, H. F. O'Connor, M. J. Benedik, T. K. Wood, Bacterial persistence increases as environmental fitness decreases. Microb. Biotechnol. 5, 509-522 (2012). doi: 10.1111/j.1751-7915.2011.00327.x; pmid: 22221537
56. V. Hauryliuk, G. C. Atkinson, K. S. Murakami, T. Tenson, K. Gerdes, Recent functional insights into the role of (p) ppGpp in bacterial physiology. Nat. Rev. Microbiol. 13, 298-309 (2015). doi: 10.1038/nrmicro3448; pmid: 25853779
57. U. Mechold, K. Potrykus, H. Murphy, K. S. Murakami, M. Cashel, Differential regulation by ppGpp versus pppGpp in Escherichia coli. Nucleic Acids Res. 41, 6175-6189 (2013). doi: 10.1093/nar/gkt302; pmid: 23620295
58. U. Kanjee, K. Ogata, W. A. Houry, Direct binding targets of the stringent response alarmone (p)ppGpp. Mol. Microbiol. 85, 1029-1043 (2012). doi: 10.1111/j.1365-2958.2012.08177.x; pmid: 22812515
59. D. Nguyen et al., Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 334, 982-986 (2011). doi: 10.1126/science.1211037; pmid: 22096200
60. D. Viducic et al., Functional analysis of spoT, relA and dksA genes on quinolone tolerance in Pseudomonas aeruginosa under nongrowing condition. Microbiol. Immunol. 50, 349-357 (2006). doi: 10.1111/j.1348-0421.2006.tb03793.x; pmid: 16625057
61. A. O. Gaca, C. Colomer-Winter, J. A. Lemos, Many means to a common end: The intricacies of (p)ppGpp metabolism and its control of bacterial homeostasis. J. Bacteriol. 197, 1146-1156 (2015). doi: 10.1128/JB.02577-14; pmid: 25605304
62. R. M. Corrigan, L. E. Bellows, A. Wood, A. Gründling, ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria. Proc. Natl. Acad. Sci. U.S.A. 113, E1710-E1719 (2016). doi: 10.1073/pnas.1522179113; pmid: 26951678
63. B. P. Conlon et al., Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat. Microbiol. 1, 16051 (2016). doi: 10.1038/nmicrobiol.2016.51
64. P. S. Stewart, Antimicrobial tolerance in biofilms. Microbiol. Spectr. 3, MB-0010-2014 (2015). pmid: 26185072
65. A. L. Spoering, K. Lewis, Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. J. Bacteriol. 183, 6746-6751 (2001). doi: 10.1128/JB.183.23.6746-6751.2001; pmid: 11698361
66. P. S. Stewart et al., Contribution of stress responses to antibiotic tolerance in Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 59, 3838-3847 (2015). doi: 10.1128/AAC.00433-15; pmid: 25870065
67. S. P. Bernier et al., Starvation, together with the SOS response, mediates high biofilm-specific tolerance to the fluoroquinolone ofloxacin. PLOS Genet. 9, e1003144 (2013). doi: 10.1371/journal.pgen.1003144; pmid: 23300476
68. A. Boehm et al., Second messenger signalling governs Escherichia coli biofilm induction upon ribosomal stress. Mol. Microbiol. 72, 1500-1516 (2009). doi: 10.1111/ j.1365-2958.2009.06739.x; pmid: 19460094
69. J. M. Navarro Llorens, A. Tormo, E. Martínez-García, Stationary phase in Gram-negative bacteria. FEMS Microbiol. Rev. 34, 476-495 (2010). doi: 10.1111/j.1574- 6976.2010.00213.x; pmid: 20236330
70. R. Hengge, Stationary-phase gene regulation in Escherichia coli. Ecosal Plus 10.1128/ecosalplus.5.6.3 (2011). doi: 10.1128/ecosalplus.5.6.3; pmid: 26442507
71. I. Keren, N. Kaldalu, A. Spoering, Y. Wang, K. Lewis, Persister cells and tolerance to antimicrobials. FEMS Microbiol. Lett. 230, 13-18 (2004). doi: 10.1016/S0378-1097(03)00856-5; pmid: 14734160
72. I. Keren, S. Minami, E. Rubin, K. Lewis, Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. mBio 2, e00100-11 (2011). doi: 10.1128/ mBio.00100-11; pmid: 21673191
73. S. M. Amato, M. A. Orman, M. P. Brynildsen, Metabolic control of persister formation in Escherichia coli. Mol. Cell 50, 475-487 (2013). doi: 10.1016/j.molcel.2013.04.002; pmid: 23665232
74. A. Battesti, N. Majdalani, S. Gottesman, The RpoS-mediated general stress response in Escherichia coli. Annu. Rev. Microbiol. 65, 189-213 (2011). doi: 10.1146/annurev-micro- 090110-102946; pmid: 21639793
75. N. Wu et al., Ranking of persister genes in the same Escherichia coli genetic background demonstrates varying importance of individual persister genes in tolerance to different antibiotics. Front. Microbiol. 6, 1003 (2015). doi: 10.3389/fmicb.2015.01003; pmid: 26483762
76. K. Murakami et al., Role for rpoS gene of Pseudomonas aeruginosa in antibiotic tolerance. FEMS Microbiol. Lett. 242, 161-167 (2005). doi: 10.1016/j.femsle.2004.11.005; pmid: 15621433
77. S. Hansen, K. Lewis, M. Vulić, Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrob. Agents Chemother. 52, 2718-2726 (2008). doi: 10.1128/AAC.00144-08; pmid: 18519731
78. Z. Baharoglu, D. Mazel, SOS, the formidable strategy of bacteria against aggressions. FEMS Microbiol. Rev. 38, 1126-1145 (2014). doi: 10.1111/1574-6976.12077; pmid: 24923554
79. K. G. Völzing, M. P. Brynildsen, Stationary-phase persisters to ofloxacin sustain DNA damage and require repair systems only during recovery. mBio 6, e00731-15 (2015). doi: 10.1128/ mBio.00731-15; pmid: 26330511
80. N. Möker, C. R. Dean, J. Tao, Pseudomonas aeruginosa increases formation of multidrug-tolerant persister cells in response to quorum-sensing signaling molecules. J. Bacteriol. 192, 1946-1955 (2010). doi: 10.1128/JB.01231-09; pmid: 20097861
81. V. Leung, C. M. Lévesque, A stress-inducible quorum-sensing peptide mediates the formation of persister cells with noninherited multidrug tolerance. J. Bacteriol. 194, 2265-2274 (2012). doi: 10.1128/JB.06707-11; pmid: 22366415
82. J. Kim, W. Park, Indole: A signaling molecule or a mere metabolic byproduct that alters bacterial physiology at a high concentration? J. Microbiol. 53, 421-428 (2015). doi: 10.1007/s12275-015-5273-3; pmid: 26115989
83. H. Luidalepp, A. Jõers, N. Kaldalu, T. Tenson, Age of inoculum strongly influences persister frequency and can mask effects of mutations implicated in altered persistence. J. Bacteriol. 193, 3598-3605 (2011). doi: 10.1128/JB.00085-11; pmid: 21602347
84. I. Keren, D. Shah, A. Spoering, N. Kaldalu, K. Lewis, Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 186, 8172-8180 (2004). doi: 10.1128/JB.186.24.8172-8180.2004; pmid: 15576765
85. R. Page, W. Peti, Toxin-antitoxin systems in bacterial growth arrest and persistence. Nat. Chem. Biol. 12, 208-214 (2016). doi: 10.1038/nchembio.2044; pmid: 26991085
86. K. Gerdes, E. Maisonneuve, Bacterial persistence and toxinantitoxin loci. Annu. Rev. Microbiol. 66, 103-123 (2012). doi: 10.1146/annurev-micro-092611-150159; pmid: 22994490
87. R. Brielle, M. L. Pinel-Marie, B. Felden, Linking bacterial type I toxins with their actions. Curr. Opin. Microbiol. 30, 114-121 (2016). doi: 10.1016/j.mib.2016.01.009; pmid: 26874964
88. K. Gerdes, E. G. Wagner, RNA antitoxins. Curr. Opin. Microbiol. 10, 117-124 (2007). doi: 10.1016/j.mib.2007.03.003; pmid: 17376733
89. A. M. Cheverton et al., A Salmonella toxin promotes persister formation through acetylation of tRNA. Mol. Cell 63, 86-96 (2016). doi: 10.1016/j.molcel.2016.05.002; pmid: 27264868
90. K. Winther, J. J. Tree, D. Tollervey, K. Gerdes, VapCs of Mycobacterium tuberculosis cleave RNAs essential for translation. Nucleic Acids Res. 10.1093/nar/gkw781 (2016). pmid: 27599842
91. I. Brzozowska, U. Zielenkiewicz, Regulation of toxin-antitoxin systems by proteolysis. Plasmid 70, 33-41 (2013). doi: 10.1016/j.plasmid.2013.01.007; pmid: 23396045
92. S. Hansen et al., Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis. PLOS ONE 7, e39185 (2012). doi: 10.1371/journal.pone.0039185; pmid: 22720069
93. X. Wang, T. K. Wood, Toxin-antitoxin systems influence biofilm and persister cell formation and the general stress response. Appl. Environ. Microbiol. 77, 5577-5583 (2011). doi: 10.1128/AEM.05068-11; pmid: 21685157
94. H. Tamman, A. Ainelo, K. Ainsaar, R. Hõrak, A moderate toxin, GraT, modulates growth rate and stress tolerance of Pseudomonas putida. J. Bacteriol. 196, 157-169 (2014). doi: 10.1128/JB.00851-13; pmid: 24163334
95. B. W. Kwan et al., The MqsR/MqsA toxin/antitoxin system protects Escherichia coli during bile acid stress. Environ. Microbiol. 17, 3168-3181 (2015). doi: 10.1111/ 1462-2920.12749; pmid: 25534751
96. E. Rotem et al., Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Proc. Natl. Acad. Sci. U.S.A. 107, 12541-12546 (2010). doi: 10.1073/pnas.1004333107; pmid: 20616060
97. I. Cataudella, A. Trusina, K. Sneppen, K. Gerdes, N. Mitarai, Conditional cooperativity in toxin-antitoxin regulation prevents random toxin activation and promotes fast translational recovery. Nucleic Acids Res. 40, 6424-6434 (2012). doi: 10.1093/nar/gks297; pmid: 22495927
98. N. Vázquez-Laslop, H. Lee, A. A. Neyfakh, Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. J. Bacteriol. 188, 3494-3497 (2006). doi: 10.1128/JB.188.10.3494-3497.2006; pmid: 16672603
99. N. D. Walter et al., Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis. J. Infect. Dis. 212, 990-998 (2015). doi: 10.1093/infdis/jiv149; pmid: 25762787
100. B. W. Kwan, J. A. Valenta, M. J. Benedik, T. K. Wood, Arrested protein synthesis increases persister-like cell formation. Antimicrob. Agents Chemother. 57, 1468-1473 (2013). doi: 10.1128/AAC.02135-12; pmid: 23295927
101. V. N. De Groote et al., Novel persistence genes in Pseudomonas aeruginosa identified by high-throughput screening. FEMS Microbiol. Lett. 297, 73-79 (2009). doi: 10.1111/j.1574-6968.2009.01657.x; pmid: 19508279
102. Y. Shan, D. Lazinski, S. Rowe, A. Camilli, K. Lewis, Genetic basis of persister tolerance to aminoglycosides in Escherichia coli. mBio 6, e00078-15 (2015). doi: 10.1128/mBio.00078-15; pmid: 25852159
103. J. J. Harrison et al., The chromosomal toxin gene yafQ is a determinant of multidrug tolerance for Escherichia coli growing in a biofilm. Antimicrob. Agents Chemother. 53, 2253-2258 (2009). doi: 10.1128/AAC.00043-09; pmid: 19307375
104. D. W. Holden, Persisters unmasked. Science 347, 30-32 (2015). doi: 10.1126/science.1262033; pmid: 25554777
105. R. Singh, C. E. Barry III, H. I. Boshoff, The three RelE homologs of Mycobacterium tuberculosis have individual, drug-specific effects on bacterial antibiotic tolerance. J. Bacteriol. 192, 1279-1291 (2010). doi: 10.1128/ JB.01285-09; pmid: 20061486
106. D. P. Pandey, K. Gerdes, Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res. 33, 966-976 (2005). doi: 10.1093/nar/gki201; pmid: 15718296
107. E. Germain, D. Castro-Roa, N. Zenkin, K. Gerdes, Molecular mechanism of bacterial persistence by HipA. Mol. Cell 52, 248-254 (2013). doi: 10.1016/j.molcel.2013.08.045; pmid: 24095282
108. C. Tian et al., Rapid curtailing of the stringent response by toxin-antitoxin module-encoded mRNases. J. Bacteriol. 198, 1918-1926 (2016). doi: 10.1128/JB.00062-16; pmid: 27137501
109. H. S. Girgis, K. Harris, S. Tavazoie, Large mutational target size for rapid emergence of bacterial persistence. Proc. Natl. Acad. Sci. U.S.A. 109, 12740-12745 (2012). doi: 10.1073/ pnas.1205124109; pmid: 22802628
110. D. Lobato-Márquez, I. Moreno-Córdoba, V. Figueroa, R. Díaz-Orejas, F. García-del Portillo, Distinct type I and type II toxin-antitoxin modules control Salmonella lifestyle inside eukaryotic cells. Sci. Rep. 5, 9374 (2015). doi: 10.1038/ srep09374; pmid: 25792384
111. A. Sala, P. Bordes, P. Genevaux, Multiple toxin-antitoxin systems in Mycobacterium tuberculosis. Toxins (Basel) 6, 1002-1020 (2014). doi: 10.3390/toxins6031002; pmid: 24662523
112. H. R. Ramage, L. E. Connolly, J. S. Cox, Comprehensive functional analysis of Mycobacterium tuberculosis toxinantitoxin systems: Implications for pathogenesis, stress responses, and evolution. PLOS Genet. 5, e1000767 (2009). doi: 10.1371/journal.pgen.1000767; pmid: 20011113
113. P. Tiwari et al., MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs. Nat. Commun. 6, 6059 (2015). doi: 10.1038/ncomms7059; pmid: 25608501
114. Y. Shao et al., TADB: A web-based resource for Type 2 toxin- antitoxin loci in bacteria and archaea. Nucleic Acids Res. 39 (suppl. 1), D606-D611 (2011). doi: 10.1093/nar/gkq908; pmid: 20929871
115. S. L. McKay, D. A. Portnoy, Ribosome hibernation facilitates tolerance of stationary-phase bacteria to aminoglycosides. Antimicrob. Agents Chemother. 59, 6992-6999 (2015). doi: 10.1128/AAC.01532-15; pmid: 26324267
116. J. R. Pohlhaus, K. N. Kreuzer, Norfloxacin-induced DNA gyrase cleavage complexes block Escherichia coli replication forks, causing double-stranded breaks in vivo. Mol. Microbiol. 56, 1416-1429 (2005). doi: 10.1111/j.1365-2958.2005.04638.x; pmid: 15916595
117. J. DeNapoli, A. K. Tehranchi, J. D. Wang, Dosedependent reduction of replication elongation rate by (p)ppGpp in Escherichia coli and Bacillus subtilis. Mol. Microbiol. 88, 93-104 (2013). doi: 10.1111/mmi.12172; pmid: 23461544
118. H. Cho, T. Uehara, T. G. Bernhardt, Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell 159, 1300-1311 (2014). doi: 10.1016/j.cell.2014.11.017; pmid: 25480295
119. Y. Pu et al., Enhanced efflux activity facilitates drug tolerance in dormant bacterial cells. Mol. Cell 62, 284-294 (2016). doi: 10.1016/j.molcel.2016.03.035; pmid: 27105118
120. Y. Liu, J. A. Imlay, Cell death from antibiotics without the involvement of reactive oxygen species. Science 339, 1210-1213 (2013). doi: 10.1126/science.1232751; pmid: 23471409
121. I. Keren, Y. Wu, J. Inocencio, L. R. Mulcahy, K. Lewis, Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science 339, 1213-1216 (2013). doi: 10.1126/ science.1232688; pmid: 23471410
122. M. Khakimova, H. G. Ahlgren, J. J. Harrison, A. M. English, D. Nguyen, The stringent response controls catalases in Pseudomonas aeruginosa and is required for hydrogen peroxide and antibiotic tolerance. J. Bacteriol. 195, 2011-2020 (2013). doi: 10.1128/JB.02061-12; pmid: 23457248
123. C. Ma et al., 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 (2010). doi: 10.1111/j.1574- 6968.2009.01857.x; pmid: 20041955
124. W. Wang et al., Transposon mutagenesis identifies novel genes associated with Staphylococcus aureus persister formation. Front. Microbiol. 6, 1437 (2015). pmid: 26779120
125. M. A. Orman, M. P. Brynildsen, Inhibition of stationary phase respiration impairs persister formation in E. coli. Nat. Commun. 6, 7983 (2015). doi: 10.1038/ncomms8983; pmid: 26246187
126. J. S. Kim et al., Fumarate-mediated persistence of Escherichia coli against antibiotics. Antimicrob. Agents Chemother. 60, 2232-2240 (2016). doi: 10.1128/AAC.01794-15; pmid: 26810657
127. A. L. Spoering, M. Vulic, K. Lewis, GlpD and PlsB participate in persister cell formation in Escherichia coli. J. Bacteriol. 188, 5136-5144 (2006). doi: 10.1128/JB.00369-06; pmid: 16816185
128. S. S. Epstein, Microbial awakenings. Nature 457, 1083 (2009). doi: 10.1038/4571083a; pmid: 19242455
129. A. Jõers, N. Kaldalu, T. Tenson, The frequency of persisters in Escherichia coli reflects the kinetics of awakening from dormancy. J. Bacteriol. 192, 3379-3384 (2010). doi: 10.1128/ JB.00056-10; pmid: 20435730
130. M. A. Schumacher et al., Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance. Cell Reports 2, 518-525 (2012). doi: 10.1016/j.celrep.2012.08.013; pmid: 22999936
131. A. Theodore, K. Lewis, M. Vulic, Tolerance of Escherichia coli to fluoroquinolone antibiotics depends on specific components of the SOS response pathway. Genetics 195, 1265-1276 (2013). doi: 10.1534/genetics.113.152306; pmid: 24077306
132. E. Wexselblatt et al., Relacin, a novel antibacterial agent targeting the Stringent Response. PLOS Pathog. 8, e1002925 (2012). doi: 10.1371/journal.ppat.1002925; pmid: 23028324
133. B. P. Conlon et al., Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365-370 (2013). doi: 10.1038/nature12790; pmid: 24226776
134. N. Chowdhury, B. W. Kwan, T. K. Wood, Persistence increases in the absence of the alarmone guanosine tetraphosphate by reducing cell growth. Sci. Rep. 6, 20519 (2016). doi: 10.1038/ srep20519; pmid: 26837570