Nutrient Depletion and Bacterial Persistence

  • Wendy W. K. MokEmail author
  • Mark P. BrynildsenEmail author


Most antibiotics do not work well on starving bacteria. In environments that are missing one or more essential nutrient, bacteria shut down the growth-related processes that most antibiotics target and ready themselves for stressful times. Such nutrient-depleted conditions can occur within a host, and they are prevalent within biofilms. For antibiotics that retain some bactericidal activity against starved populations, treatments of those cultures often leave many persisters, which can go on to spawn new populations. Persisters are bacterial cells with non-inherited abilities to survive antibiotic treatments that kill the majority of their genetically identical kin. The capacity of persisters to tolerate such treatments originates from phenotypic differences between them and the bacteria that die, and understanding those survival mechanisms promises to improve treatments for chronic and recurring infections. Here we review knowledge of bacterial starvation physiology and provide an overview of nutritional challenges bacteria face in the host and in biofilms. We then describe those antibiotic classes with the capacity to kill nutrient-deprived bacteria and summarize understanding of persistence in those populations. Finally, we discuss approaches that could be used to develop treatments that eradicate starved bacterial populations and the persisters within them.


Persister Starvation Stationary phase Biofilm Fluoroquinolone 



This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (M.P.B: R21AI117009, R01AI130293), the Charles H. Revson Foundation (W.W.K.M.: Fellowship in Biomedical Science), and Princeton University (M.P.B.: startup funds). This content is solely the responsibility of the authors and does not necessarily represent the views of the funding agencies. The authors declare no conflicts of interest.


  1. Abdel-Nour, M., Duncan, C., Low, D. E., & Guyard, C. (2013). Biofilms: The stronghold of Legionella pneumophila. International Journal of Molecular Sciences, 14, 21660–21675.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Akerlund, T., Nordstrom, K., & Bernander, R. (1995). Analysis of cell size and DNA content in exponentially growing and stationary-phase batch cultures of Escherichia coli. Journal of Bacteriology, 177, 6791–6797.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.PubMedPubMedCentralGoogle Scholar
  4. Alteri, C. J., & Mobley, H. L. (2012). Escherichia coli physiology and metabolism dictates adaptation to diverse host microenvironments. Current Opinion in Microbiology, 15, 3–9.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.Google Scholar
  6. 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. Frontiers in Microbiology, 5, 70.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Appelberg, R. (2006). Macrophage nutriprive antimicrobial mechanisms. Journal of Leukocyte Biology, 79, 1117–1128.PubMedCrossRefGoogle Scholar
  8. Armstrong, E. S., & Miller, G. H. (2010). Combating evolution with intelligent design: The neoglycoside ACHN-490. Current Opinion in Microbiology, 13, 565–573.PubMedCrossRefGoogle Scholar
  9. Ault-Riche, D., Fraley, C. D., Tzeng, C. M., & Kornberg, A. (1998). Novel assay reveals multiple pathways regulating stress-induced accumulations of inorganic polyphosphate in Escherichia coli. Journal of Bacteriology, 180, 1841–1847.PubMedPubMedCentralGoogle Scholar
  10. Baba, T., Ara, T., Hasegawa, M., Takai, Y., Okumura, Y., Baba, M., Datsenko, K. A., Tomita, M., Wanner, B. L., & Mori, H. (2006). Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: The Keio collection. Molecular Systems Biology, 2, 2006.0008.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bahar, A. A., & Ren, D. (2013). Antimicrobial peptides. Pharmaceuticals (Basel), 6, 1543–1575.CrossRefGoogle Scholar
  12. Balaban, N. Q. (2011). Persistence: Mechanisms for triggering and enhancing phenotypic variability. Current Opinion in Genetics & Development, 21, 768–775.CrossRefGoogle Scholar
  13. Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., & Leibler, S. (2004). Bacterial persistence as a phenotypic switch. Science, 305, 1622–1625.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. Ballesteros, M., Fredriksson, A., Henriksson, J., & Nystrom, T. (2001). Bacterial senescence: Protein oxidation in non-proliferating cells is dictated by the accuracy of the ribosomes. The EMBO Journal, 20, 5280–5289.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Barak, Z., Gallant, J., Lindsley, D., Kwieciszewki, B., & Heidel, D. (1996). Enhanced ribosome frameshifting in stationary phase cells. Journal of Molecular Biology, 263, 140–148.PubMedCrossRefPubMedCentralGoogle Scholar
  17. Barrett, T. C., Mok, W. W. K., Murawski, A. M., & Brynildsen, M. P. (2019). Enhanced antibiotic resistance development from fluoroquinolone persisters after a single exposure to antibiotic. Nature Communications, 10(1), 1177.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Beisel, W. R. (1975). Metabolic response to infection. Annual Review of Medicine, 26, 9–20.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Belkaid, Y., & Segre, J. A. (2014). Dialogue between skin microbiota and immunity. Science, 346, 954–959.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Bergkessel, M., Basta, D. W., & Newman, D. K. (2016). The physiology of growth arrest: Uniting molecular and environmental microbiology. Nature Reviews. Microbiology, 14, 549–562.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Blaser, M. J., & Falkow, S. (2009). What are the consequences of the disappearing human microbiota? Nature Reviews. Microbiology, 7, 887–894.PubMedCrossRefPubMedCentralGoogle Scholar
  22. Boradia, V. M., Malhotra, H., Thakkar, J. S., Tillu, V. A., Vuppala, B., Patil, P., Sheokand, N., Sharma, P., Chauhan, A. S., Raje, M., & Raje, C. I. (2014). Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin. Nature Communications, 5, 4730.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Bougdour, A., & Gottesman, S. (2007). ppGpp regulation of RpoS degradation via anti-adaptor protein IraP. Proceedings of the National Academy of Sciences of the United States of America, 104, 12896–12901.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Bougdour, A., Wickner, S., & Gottesman, S. (2006). Modulating RssB activity: IraP, a novel regulator of sigma(S) stability in Escherichia coli. Genes and Development, 20, 884–897.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Bougdour, A., Cunning, C., Baptiste, P. J., Elliott, T., & Gottesman, S. (2008). Multiple pathways for regulation of sigmas (RpoS) stability in Escherichia coli via the action of multiple anti-adaptors. Molecular Microbiology, 68, 298–313.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Brauer, M. J., Yuan, J., Bennett, B. D., Lu, W., Kimball, E., Botstein, D., & Rabinowitz, J. D. (2006). Conservation of the metabolomic response to starvation across two divergent microbes. Proceedings of the National Academy of Sciences of the United States of America, 103, 19302–19307.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. Brooks, T., & Keevil, C. W. (1997). A simple artificial urine for the growth of urinary pathogens. Letters in Applied Microbiology, 24, 203–206.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Brown, S. A., Palmer, K. L., & Whiteley, M. (2008). Revisiting the host as a growth medium. Nature Reviews. Microbiology, 6, 657–666.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Buhmann, M. T., Stiefel, P., Maniura-Weber, K., & Ren, Q. (2016). In vitro biofilm models for device-related infections. Trends in Biotechnology, 34, 945–948.PubMedCrossRefPubMedCentralGoogle Scholar
  31. Chubukov, V., & Sauer, U. (2014). Environmental dependence of stationary-phase metabolism in Bacillus subtilis and Escherichia coli. Applied and Environmental Microbiology, 80, 2901–2909.Google Scholar
  32. Conlon, B. P., Nakayasu, E. S., Fleck, L. E., Lafleur, M. D., Isabella, V. M., Coleman, K., Leonard, S. N., Smith, R. D., Adkins, J. N., & Lewis, K. (2013). Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature, 503, 365–370.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Cozens, R. M., Tuomanen, E., Tosch, W., Zak, O., Suter, J., & Tomasz, A. (1986). Evaluation of the bactericidal activity of beta-lactam antibiotics on slowly growing bacteria cultured in the chemostat. Antimicrobial Agents and Chemotherapy, 29, 797–802.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Cui, P., Niu, H., Shi, W., Zhang, S., Zhang, H., Margolick, J., Zhang, W., & Zhang, Y. (2016). Disruption of membrane by colistin kills uropathogenic Escherichia coli persisters and enhances killing of other antibiotics. Antimicrobial Agents and Chemotherapy, 60, 6867–6871.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Culp, E., & Wright, G. D. (2017). Bacterial proteases, untapped antimicrobial drug targets. Journal of Antibiotics (Tokyo), 70, 366–377.CrossRefGoogle Scholar
  36. Damerau, K., & St John, A. C. (1993). Role of Clp protease subunits in degradation of carbon starvation proteins in Escherichia coli. Journal of Bacteriology, 175, 53–63.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Davis, B. D. (1987). Mechanism of bactericidal action of aminoglycosides. Microbiological Reviews, 51, 341–350.PubMedPubMedCentralGoogle Scholar
  38. De Beer, D., Stoodley, P., Roe, F., & Lewandowski, Z. (1994). Effects of biofilm structures on oxygen distribution and mass transport. Biotechnology and Bioengineering, 43, 1131–1138.PubMedCrossRefPubMedCentralGoogle Scholar
  39. De Sanctis, J., Teixeira, L., Van Duin, D., Odio, C., Hall, G., Tomford, J. W., Perez, F., Rudin, S. D., Bonomo, R. A., Barsoum, W. K., Joyce, M., Krebs, V., & Schmitt, S. (2014). Complex prosthetic joint infections due to carbapenemase-producing Klebsiella pneumoniae: A unique challenge in the era of untreatable infections. International Journal of Infectious Diseases, 25, 73–78.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Dethlefsen, L., & Relman, D. A. (2011). Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proceedings of the National Academy of Sciences of the United States of America, 108(Suppl 1), 4554–4561.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Dillon, N. A., Peterson, N. D., Feaga, H. A., Keiler, K. C., & Baughn, A. D. (2017). Anti-tubercular activity of pyrazinamide is independent of trans-translation and RpsA. Scientific Reports, 7, 6135.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Dong, F., Wang, B., Zhang, L., Tang, H., Li, J., & Wang, Y. (2012). Metabolic response to Klebsiella pneumoniae infection in an experimental rat model. PLoS One, 7, E51060.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Doucette, C. D., Schwab, D. J., Wingreen, N. S., & Rabinowitz, J. D. (2011). Alpha-ketoglutarate coordinates carbon and nitrogen utilization via enzyme I inhibition. Nature Chemical Biology, 7, 894–901.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Drlica, K., & Zhao, X. (1997). DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiology and Molecular Biology Review, 61, 377–392.Google Scholar
  45. Drlica, K., Malik, M., Kerns, R. J., & Zhao, X. (2008). Quinolone-mediated bacterial death. Antimicrobial Agents and Chemotherapy, 52, 385–392.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Durfee, T., Hansen, A. M., Zhi, H., Blattner, F. R., & Jin, D. J. (2008). Transcription profiling of the stringent response in Escherichia coli. Journal of Bacteriology, 190, 1084–1096.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Ehlers, S., & Schaible, U. E. (2012). The granuloma in tuberculosis: Dynamics of a host-pathogen collusion. Frontiers in Immunology, 3, 411.PubMedPubMedCentralGoogle Scholar
  48. Eng, R. H., Padberg, F. T., Smith, S. M., Tan, E. N., & Cherubin, C. E. (1991). Bactericidal effects of antibiotics on slowly growing and nongrowing bacteria. Antimicrobial Agents and Chemotherapy, 35, 1824–1828.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Escoll, P., & Buchrieser, C. (2018). Metabolic reprogramming of host cells upon bacterial infection: Why shift to a warburg-like metabolism? The FEBS Journal, 285, 2146–2160.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Escoll, P., Song, O. R., Viana, F., Steiner, B., Lagache, T., Olivo-Marin, J. C., Impens, F., Brodin, P., Hilbi, H., & Buchrieser, C. (2017). Legionella pneumophila modulates mitochondrial dynamics to trigger metabolic repurposing of infected macrophages. Cell Host and Microbe, 22, 302–316.E7.PubMedCrossRefPubMedCentralGoogle Scholar
  51. Evangelopoulos, D., Da Fonseca, J. D., & Waddell, S. J. (2015). Understanding anti-tuberculosis drug efficacy: Rethinking bacterial populations and how we model them. International Journal of Infectious Diseases, 32, 76–80.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Farewell, A., Diez, A. A., Dirusso, C. C., & Nystrom, T. (1996). Role of the Escherichia coli FadR regulator in stasis survival and growth phase-dependent expression of the UspA, fad, and fab genes. Journal of Bacteriology, 178, 6443–6450.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Feist, A. M., Henry, C. S., Reed, J. L., Krummenacker, M., Joyce, A. R., Karp, P. D., Broadbelt, L. J., Hatzimanikatis, V., & Palsson, B. O. (2007). A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information. Molecular Systems Biology, 3, 121.Google Scholar
  54. Finkel, S. E. (2006). Long-term survival during stationary phase: Evolution and the GASP phenotype. Nature Reviews. Microbiology, 4, 113–120.PubMedCrossRefPubMedCentralGoogle Scholar
  55. Flemming, H. C., & Wingender, J. (2010). The biofilm matrix. Nature Reviews. Microbiology, 8, 623–633.PubMedCrossRefPubMedCentralGoogle Scholar
  56. Folsom, J. P., Richards, L., Pitts, B., Roe, F., Ehrlich, G. D., Parker, A., Mazurie, A., & Stewart, P. S. (2010). Physiology of Pseudomonas aeruginosa in biofilms as revealed by transcriptome analysis. BMC Microbiology, 10, 294.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Fonseca, M. V., & Swanson, M. S. (2014). Nutrient salvaging and metabolism by the intracellular pathogen Legionella pneumophila. Frontiers in Cellular and Infection Microbiology, 4, 12.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Freyberg, Z., & Harvill, E. T. (2017). Pathogen manipulation of host metabolism: A common strategy for immune evasion. PLoS Pathogens, 13, e1006669.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Fung, D. K., Chan, E. W., Chin, M. L., & Chan, R. C. (2010). Delineation of a bacterial starvation stress response network which can mediate antibiotic tolerance development. Antimicrobial Agents and Chemotherapy, 54, 1082–1093.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Gavrish, E., Sit, C. S., Cao, S., Kandror, O., Spoering, A., Peoples, A., Ling, L., Fetterman, A., Hughes, D., Bissell, A., Torrey, H., Akopian, T., Mueller, A., Epstein, S., Goldberg, A., Clardy, J., & Lewis, K. (2014). Lassomycin, a ribosomally synthesized cyclic peptide, kills Mycobacterium tuberculosis by targeting the ATP-dependent protease Clpc1p1p2. Chemistry and Biology, 21, 509–518.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Gefen, O., & Balaban, N. Q. (2009). The importance of being persistent: Heterogeneity of bacterial populations under antibiotic stress. FEMS Microbiology Reviews, 33, 704–717.PubMedCrossRefGoogle Scholar
  62. Gefen, O., Fridman, O., Ronin, I., & Balaban, N. Q. (2014). Direct observation of single stationary-phase bacteria reveals a surprisingly long period of constant protein production activity. Proceedings of the National Academy of Sciences of the United States of America, 111, 556–561.PubMedCrossRefGoogle Scholar
  63. Gengenbacher, M., & Kaufmann, S. H. (2012). Mycobacterium tuberculosis: Success through dormancy. FEMS Microbiology Reviews, 36, 514–532.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Gold, B., & Nathan, C. (2017). Targeting phenotypically tolerant Mycobacterium tuberculosis. Microbiology Spectrum, 5.
  65. Gorke, B., & Stulke, J. (2008). Carbon catabolite repression in bacteria: Many ways to make the most out of nutrients. Nature Reviews. Microbiology, 6, 613–624.PubMedCrossRefPubMedCentralGoogle Scholar
  66. Gottesman, S., & Maurizi, M. R. (2001). Cell biology. Surviving starvation. Science, 293, 614–615.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Groat, R. G., Schultz, J. E., Zychlinsky, E., Bockman, A., & Matin, A. (1986). Starvation proteins in Escherichia coli: Kinetics of synthesis and role in starvation survival. Journal of Bacteriology, 168, 486–493.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Guido, N. J., Wang, X., Adalsteinsson, D., Mcmillen, D., Hasty, J., Cantor, C. R., Elston, T. C., & Collins, J. J. (2006). A bottom-up approach to gene regulation. Nature, 439, 856–860.PubMedCrossRefPubMedCentralGoogle Scholar
  69. Guido, N. J., Lee, P., Wang, X., Elston, T. C., & Collins, J. J. (2007). A pathway and genetic factors contributing to elevated gene expression noise in stationary phase. Biophysical Journal, 93, L55–L57.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 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.CrossRefGoogle Scholar
  71. Haase, I., Sarge, S., Illarionov, B., Laudert, D., Hohmann, H. P., Bacher, A., & Fischer, M. (2013). Enzymes from the haloacid dehalogenase (HAD) superfamily catalyse the elusive dephosphorylation step of riboflavin biosynthesis. Chembiochem, 14, 2272–2275.PubMedCrossRefGoogle Scholar
  72. Hall-Stoodley, L., Costerton, J. W., & Stoodley, P. (2004). Bacterial biofilms: From the natural environment to infectious diseases. Nature Reviews. Microbiology, 2, 95–108.PubMedCrossRefGoogle Scholar
  73. Hansen, S., Lewis, K., & Vulic, M. (2008). Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrobial Agents and Chemotherapy, 52, 2718–2726.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Held, T. K., Weihua, X., Yuan, L., Kalvakolanu, D. V., & Cross, A. S. (1999). Gamma interferon augments macrophage activation by lipopolysaccharide by two distinct mechanisms, at the signal transduction level and via an autocrine mechanism involving tumor necrosis factor alpha and interleukin-1. Infection and Immunity, 67, 206–212.Google Scholar
  75. Henry, T. C., & Brynildsen, M. P. (2016). Development of persister-FACSeq: A method to massively parallelize quantification of persister physiology and its heterogeneity. Scientific Reports, 6, 25100.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Holden, V. I., Breen, P., Houle, S., Dozois, C. M., & Bachman, M. A. (2016). Klebsiella pneumoniae siderophores induce inflammation, bacterial dissemination, and HIF-1α stabilization during pneumonia. MBio, 7, e01397-16.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Hu, Y., & Coates, A. (2012). Nonmultiplying bacteria are profoundly tolerant to antibiotics. Handbook of experimental pharmacology, 99–119.Google Scholar
  78. Hu, Y., Coates, A. R., & Mitchison, D. A. (2006). Sterilising action of pyrazinamide in models of dormant and rifampicin-tolerant Mycobacterium tuberculosis. The International Journal of Tuberculosis and Lung Disease, 10, 317–322.PubMedGoogle Scholar
  79. Hu, Y., Shamaei-Tousi, A., Liu, Y., & Coates, A. (2010). A new approach for the discovery of antibiotics by targeting non-multiplying bacteria: A novel topical antibiotic for staphylococcal infections. PLoS One, 5, e11818.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Huang, Y., Nishikawa, T., Satoh, K., Iwata, T., Fukushima, T., Santa, T., Homma, H., & Imai, K. (1998). Urinary excretion of D-serine in human: Comparison of different ages and species. Biological and Pharmaceutical Bulletin, 21, 156–162.PubMedCrossRefGoogle Scholar
  81. Hurdle, J. G., O’neill, A. J., Chopra, I., & Lee, R. E. (2011). Targeting bacterial membrane function: An underexploited mechanism for treating persistent infections. Nature Reviews. Microbiology, 9, 62–75.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Irr, J. D. (1972). Control of nucleotide metabolism and ribosomal ribonucleic acid synthesis during nitrogen starvation of Escherichia coli. Journal of Bacteriology, 110, 554–561.PubMedPubMedCentralGoogle Scholar
  83. Isberg, R. R., O’connor, T. J., & Heidtman, M. (2009). The Legionella pneumophila replication vacuole: Making a cosy niche inside host cells. Nature Reviews. Microbiology, 7, 13–24.PubMedCrossRefGoogle Scholar
  84. James, G. A., Ge Zhao, A., Usui, M., Underwood, R. A., Nguyen, H., Beyenal, H., Delancey Pulcini, E., Agostinho Hunt, A., Bernstein, H. C., Fleckman, P., Olerud, J., Williamson, K. S., Franklin, M. J., & Stewart, P. S. (2016). Microsensor and transcriptomic signatures of oxygen depletion in biofilms associated with chronic wounds. Wound Repair and Regeneration, 24, 373–383.Google Scholar
  85. Jeanguenin, L., Lara-Nunez, A., Pribat, A., Mageroy, M. H., Gregory, J. F., 3rd, Rice, K. C., De Crecy-Lagard, V., & Hanson, A. D. (2010). Moonlighting glutamate formiminotransferases can functionally replace 5-formyltetrahydrofolate cycloligase. The Journal of Biological Chemistry, 285, 41557–41566.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Jenkins, D. E., Schultz, J. E., & Matin, A. (1988). Starvation-induced cross protection against heat or H2O2 challenge in Escherichia coli. Journal of Bacteriology, 170, 3910–3914.Google Scholar
  87. Kamada, N., Chen, G. Y., Inohara, N., & Núñez, G. (2013). Control of pathogens and pathobionts by the gut microbiota. Nature Immunology, 14, 685–690.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Keren, I., Kaldalu, N., Spoering, A., Wang, Y., & Lewis, K. (2004). Persister cells and tolerance to antimicrobials. FEMS Microbiology Letters, 230, 13–18.CrossRefGoogle Scholar
  89. Keseler, I. M., Mackie, A., Santos-Zavaleta, A., Billington, R., Bonavides-Martinez, C., Caspi, R., Fulcher, C., Gama-Castro, S., Kothari, A., Krummenacker, M., Latendresse, M., Muniz-Rascado, L., Ong, Q., Paley, S., Peralta-Gil, M., Subhraveti, P., Velazquez-Ramirez, D. A., Weaver, D., Collado-Vides, J., Paulsen, I., & Karp, P. D. (2017). The ecocyc database: Reflecting new knowledge about Escherichia coli K-12. Nucleic Acids Research, 45, D543–D550.PubMedCrossRefGoogle Scholar
  90. Kim, W., Zhu, W., Hendricks, G. L., Van Tyne, D., Steele, A. D., Keohane, C. E., Fricke, N., Conery, A. L., Shen, S., Pan, W., Lee, K., Rajamuthiah, R., Fuchs, B. B., Vlahovska, P. M., Wuest, W. M., Gilmore, M. S., Gao, H., Ausubel, F. M., & Mylonakis, E. (2018). A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature, 556, 103–107.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Kochanowski, K., Volkmer, B., Gerosa, L., Haverkorn Van Rijsewijk, B. R., Schmidt, A., & Heinemann, M. (2013). Functioning of a metabolic flux sensor in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America, 110, 1130–1135.PubMedCrossRefGoogle Scholar
  92. Koo, H., Xiao, J., Klein, M. I., & Jeon, J. G. (2010). Exopolysaccharides produced by Streptococcus mutans glucosyltransferases modulate the establishment of microcolonies within multispecies biofilms. Journal of Bacteriology, 192, 3024–3032.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Lange, R., & Hengge-Aronis, R. (1991). Identification of a central regulator of stationary-phase gene expression in Escherichia coli. Molecular Microbiology, 5, 49–59.PubMedCrossRefGoogle Scholar
  94. Lange, R., & Hengge-Aronis, R. (1994). The cellular concentration of the sigma S subunit of RNA polymerase in Escherichia coli is controlled at the levels of transcription, translation, and protein stability. Genes and Development, 8, 1600–1612.PubMedCrossRefGoogle Scholar
  95. Lewis, K. (2007). Persister cells, dormancy and infectious disease. Nature Reviews. Microbiology, 5, 48–56.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Lewis, K. (2010). Persister cells. Annual Review of Microbiology, 64, 357–372.CrossRefGoogle Scholar
  97. 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
  98. Li, S. H., Li, Z., Park, J. O., King, C. G., Rabinowitz, J. D., Wingreen, N. S., & Gitai, Z. (2018). Escherichia coli translation strategies differ across carbon, nitrogen and phosphorus limitation conditions. Nature Microbiology, 3, 939–947.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Link, H., Fuhrer, T., Gerosa, L., Zamboni, N., & Sauer, U. (2015). Real-time metabolome profiling of the metabolic switch between starvation and growth. Nature Methods, 12, 1091–1097.PubMedCrossRefGoogle Scholar
  100. Litsios, A., Ortega, A. D., Wit, E. C., & Heinemann, M. (2018). Metabolic-flux dependent regulation of microbial physiology. Current Opinion in Microbiology, 42, 71–78.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Liu, J., Prindle, A., Humphries, J., Gabalda-Sagarra, M., Asally, M., Lee, D. Y., Ly, S., Garcia-Ojalvo, J., & Suel, G. M. (2015). Metabolic co-dependence gives rise to collective oscillations within biofilms. Nature, 523, 550–554.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Lu, T. K., & Collins, J. J. (2009). Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy. Proceedings of the National Academy of Sciences of the United States of America, 106, 4629–4634.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 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
  104. Mackenzie, C. R., Hadding, U., & Däubener, W. (1998). Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. The Journal of Infectious Diseases, 178, 875–878.PubMedCrossRefPubMedCentralGoogle Scholar
  105. Makino, K., Shinagawa, H., Amemura, M., Kawamoto, T., Yamada, M., & Nakata, A. (1989). Signal transduction in the phosphate regulon of Escherichia coli involves phosphotransfer between PhoR and PhoB proteins. Journal of Molecular Biology, 210, 551–559.PubMedCrossRefPubMedCentralGoogle Scholar
  106. Mandelstam, J. (1963). Protein turnover and its function in economy of cell. Annals of the New York Academy of Sciences, 102, 621–636.CrossRefGoogle Scholar
  107. Mark Welch, J. L., Rossetti, B. J., Rieken, C. W., Dewhirst, F. E., & Borisy, G. G. (2016). Biogeography of a human oral microbiome at the micron scale. Proceedings of the National Academy of Sciences of the United States of America, 113, E791–E800.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Marks, L. R., Reddinger, R. M., & Hakansson, A. P. (2012). High levels of genetic recombination during nasopharyngeal carriage and biofilm formation in Streptococcus pneumoniae. MBio, 3, e00200-12.Google Scholar
  109. Mascio, C. T., Alder, J. D., & Silverman, J. A. (2007). Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells. Antimicrobial Agents and Chemotherapy, 51, 4255–4260.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Matin, A., Auger, E. A., Blum, P. H., & Schultz, J. E. (1989). Genetic basis of starvation survival in nondifferentiating bacteria. Annual Review of Microbiology, 43, 293–316.PubMedCrossRefPubMedCentralGoogle Scholar
  111. Meddows, T. R., Savory, A. P., Grove, J. I., Moore, T., & Lloyd, R. G. (2005). RecN protein and transcription factor DksA combine to promote faithful recombinational repair of DNA double-strand breaks. Molecular Microbiology, 57, 97–110.PubMedCrossRefPubMedCentralGoogle Scholar
  112. Melican, K., Boekel, J., Månsson, L. E., Sandoval, R. M., Tanner, G. A., Källskog, O., Palm, F., Molitoris, B. A., & Richter-Dahlfors, A. (2008). Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis. Cellular Microbiology, 10, 1987–1998.PubMedCrossRefPubMedCentralGoogle Scholar
  113. Melican, K., Sandoval, R. M., Kader, A., Josefsson, L., Tanner, G. A., Molitoris, B. A., & Richter-Dahlfors, A. (2011). Uropathogenic Escherichia coli P and type 1 fimbriae act in synergy in a living host to facilitate renal colonization leading to nephron obstruction. PLoS Pathogens, 7, e1001298.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Metzger, S., Schreiber, G., Aizenman, E., Cashel, M., & Glaser, G. (1989). Characterization of the relA1 mutation and a comparison of relA1 with new relA null alleles in Escherichia coli. The Journal of Biological Chemistry, 264, 21146–21152.PubMedPubMedCentralGoogle Scholar
  115. Meylan, S., Porter, C. B. M., Yang, J. H., Belenky, P., Gutierrez, A., Lobritz, M. A., Park, J., Kim, S. H., Moskowitz, S. M., & Collins, J. J. (2017). Carbon sources tune antibiotic susceptibility in Pseudomonas aeruginosa via tricarboxylic acid cycle control. Cell Chemical Biology, 24, 195–206.Google Scholar
  116. Meylan, S., Andrews, I. W., & Collins, J. J. (2018). Targeting antibiotic tolerance, pathogen by pathogen. Cell, 172, 1228–1238.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Mok, W. W. K., & Brynildsen, M. P. (2018). Timing of DNA damage responses impacts persistence to fluoroquinolones. Proceedings of the National Academy of Sciences of the United States of America, 115, e6301–e6309.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Mok, W. W., Park, J. O., Rabinowitz, J. D., & Brynildsen, M. P. (2015). RNA futile cycling in model persisters derived from MazF accumulation. MBio, 6, E01588–E01515.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Morohoshi, T., Maruo, T., Shirai, Y., Kato, J., Ikeda, T., Takiguchi, N., Ohtake, H., & Kuroda, A. (2002). Accumulation of inorganic polyphosphate in phoU mutants of Escherichia coli and Synechocystis sp. strain Pcc6803. Applied and Environmental Microbiology, 68, 4107–4110.Google Scholar
  120. Mulcahy, L. R., Isabella, V. M., & Lewis, K. (2014). Pseudomonas aeruginosa biofilms in disease. Microbial Ecology, 68, 1–12.PubMedCrossRefPubMedCentralGoogle Scholar
  121. Müller, A., Wenzel, M., Strahl, H., Grein, F., Saaki, T. N. V., Kohl, B., Siersma, T., Bandow, J. E., Sahl, H. G., Schneider, T., & Hamoen, L. W. (2016). Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. Proceedings of the National Academy of Sciences of the United States of America, 113, E7077–E7086.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Nair, S., & Finkel, S. E. (2004). Dps protects cells against multiple stresses during stationary phase. Journal of Bacteriology, 186, 4192–4198.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Nautiyal, A., Patil, K. N., & Muniyappa, K. (2014). Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery. The Journal of Antimicrobial Chemotherapy, 69, 1834–1843.Google Scholar
  124. Ng, K. M., Ferreyra, J. A., Higginbottom, S. K., Lynch, J. B., Kashyap, P. C., Gopinath, S., Naidu, N., Choudhury, B., Weimer, B. C., Monack, D. M., & Sonnenburg, J. L. (2013). Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature, 502, 96–99.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Notley-Mcrobb, L., Death, A., & Ferenci, T. (1997). The relationship between external glucose concentration and cAMP levels inside Escherichia coli: Implications for models of phosphotransferase-mediated regulation of adenylate cyclase. Microbiology, 143(Pt 6), 1909–1918.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Nystrom, T. (2004). Stationary-phase physiology. Annual Review of Microbiology, 58, 161–181.PubMedCrossRefPubMedCentralGoogle Scholar
  127. Nystrom, T., Larsson, C., & Gustafsson, L. (1996). Bacterial defense against aging: Role of the Escherichia coli ArcA regulator in gene expression, readjusted energy flux and survival during stasis. The EMBO Journal, 15, 3219–3228.PubMedPubMedCentralCrossRefGoogle Scholar
  128. O’Neal, C. R., Gabriel, W. M., Turk, A. K., Libby, S. J., Fang, F. C., & Spector, M. P. (1994). Rpos is necessary for both the positive and negative regulation of starvation survival genes during phosphate, carbon, and nitrogen starvation in Salmonella typhimurium. Journal of Bacteriology, 176, 4610–4616.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Olsen, I. (2005). New principles in ecological regulation—Features from the oral cavity. Microbial Ecology in Health and Disease, 18, 26–31.CrossRefGoogle Scholar
  130. Orman, M. A., & Brynildsen, M. P. (2015). Inhibition of stationary phase respiration impairs persister formation in E. coli. Nature Communications, 6, 7983.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Palmer, K. L., Mashburn, L. M., Singh, P. K., & Whiteley, M. (2005). Cystic fibrosis sputum supports growth and cues key aspects of Pseudomonas aeruginosa physiology. Journal of Bacteriology, 187, 5267–5277.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Palmer, K. L., Aye, L. M., & Whiteley, M. (2007). Nutritional cues control Pseudomonas aeruginosa multicellular behavior in cystic fibrosis sputum. Journal of Bacteriology, 189, 8079–8087.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Passalacqua, K. D., Charbonneau, M. E., & O’riordan, M. X. (2016). Bacterial metabolism shapes the host-pathogen interface. Microbiology Spectrum, 4.
  134. Percival, S. L., Suleman, L., Vuotto, C., & Donelli, G. (2015). Healthcare-associated infections, medical devices and biofilms: Risk, tolerance and control. Journal of Medical Microbiology, 64, 323–334.PubMedCrossRefPubMedCentralGoogle Scholar
  135. Pereira, F. C., & Berry, D. (2017). Microbial nutrient niches in the gut. Environmental Microbiology, 19, 1366–1378.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Perkins, S. D., Mayfield, J., Fraser, V., & Angenent, L. T. (2009). Potentially pathogenic bacteria in shower water and air of a stem cell transplant unit. Applied and Environmental Microbiology, 75, 5363–5372.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Peterson, C. N., Mandel, M. J., & Silhavy, T. J. (2005). Escherichia coli starvation diets: Essential nutrients weigh in distinctly. Journal of Bacteriology, 187, 7549–7553.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Peterson, N. D., Rosen, B. C., Dillon, N. A., & Baughn, A. D. (2015). Uncoupling environmental pH and intrabacterial acidification from pyrazinamide susceptibility in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 59, 7320–7326.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Pogliano, J., Pogliano, N., & Silverman, J. A. (2012). Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins. Journal of Bacteriology, 194, 4494–4504.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Potera, C. (1999). Forging a link between biofilms and disease. Science, 283(1837), 1839.Google Scholar
  141. Potrykus, K., & Cashel, M. (2008). (p)ppGpp: Still magical? Annual Review of Microbiology, 62, 35–51.Google Scholar
  142. Pratt, L. A., & Silhavy, T. J. (1996). The response regulator SprE controls the stability of RpoS. Proceedings of the National Academy of Sciences of the United States of America, 93, 2488–2492.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Prouty, W. F., & Goldberg, A. L. (1972). Effects of protease inhibitors on protein breakdown in Escherichia coli. The Journal of Biological Chemistry, 247, 3341–3352.PubMedPubMedCentralGoogle Scholar
  144. Radzikowski, J. L., Vedelaar, S., Siegel, D., Ortega, Á., Schmidt, A., & Heinemann, M. (2016). Bacterial persistence is an active σs stress response to metabolic flux limitation. Molecular Systems Biology, 12, 882.Google Scholar
  145. Radzikowski, J. L., Schramke, H., & Heinemann, M. (2017). Bacterial persistence from a system-level perspective. Current Opinion in Biotechnology, 46, 98–105.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Rao, N. N., & Kornberg, A. (1996). Inorganic polyphosphate supports resistance and survival of stationary-phase Escherichia coli. Journal of Bacteriology, 178, 1394–1400.PubMedPubMedCentralCrossRefGoogle Scholar
  147. Redgrave, L. S., Sutton, S. B., Webber, M. A., & Piddock, L. J. (2014). Fluoroquinolone resistance: Mechanisms, impact on bacteria, and role in evolutionary success. Trends in Microbiology, 22, 438–445.PubMedCrossRefPubMedCentralGoogle Scholar
  148. Reeve, C. A., Amy, P. S., & Matin, A. (1984a). Role of protein synthesis in the survival of carbon-starved Escherichia coli K-12. Journal of Bacteriology, 160, 1041–1046.PubMedPubMedCentralGoogle Scholar
  149. Reeve, C. A., Bockman, A. T., & Matin, A. (1984b). Role of protein degradation in the survival of carbon-starved Escherichia coli and Salmonella typhimurium. Journal of Bacteriology, 157, 758–763.Google Scholar
  150. Reffuveille, F., De La Fuente-Nunez, C., Mansour, S., & Hancock, R. E. (2014). A broad-spectrum antibiofilm peptide enhances antibiotic action against bacterial biofilms. Antimicrobial Agents and Chemotherapy, 58, 5363–5371.PubMedPubMedCentralCrossRefGoogle Scholar
  151. Reitzer, L. (2003). Nitrogen assimilation and global regulation in Escherichia coli. Annual Review of Microbiology, 57, 155–176.PubMedCrossRefPubMedCentralGoogle Scholar
  152. Ross, W., Vrentas, C. E., Sanchez-Vazquez, P., Gaal, T., & Gourse, R. L. (2013). The magic spot: A ppGpp binding site on E. coli RNA polymerase responsible for regulation of transcription initiation. Molecular Cell, 50, 420–429.PubMedPubMedCentralCrossRefGoogle Scholar
  153. Ross, W., Sanchez-Vazquez, P., Chen, A. Y., Lee, J. H., Burgos, H. L., & Gourse, R. L. (2016). PpGpp binding to a site at the RNAP-DksA interface accounts for its dramatic effects on transcription initiation during the stringent response. Molecular Cell, 62, 811–823.PubMedPubMedCentralCrossRefGoogle Scholar
  154. Salmon, K. A., Hung, S. P., Steffen, N. R., Krupp, R., Baldi, P., Hatfield, G. W., & Gunsalus, R. P. (2005). Global gene expression profiling in Escherichia coli K12: Effects of oxygen availability and ArcA. The Journal of Biological Chemistry, 280, 15084–15096.PubMedCrossRefPubMedCentralGoogle Scholar
  155. Santos, J. M., Lobo, M., Matos, A. P., De Pedro, M. A., & Arraiano, C. M. (2002). The gene bolA regulates dacA (PBP5), dacC (PBP6) and ampC (AmpC), promoting normal morphology in Escherichia coli. Molecular Microbiology, 45, 1729–1740.PubMedCrossRefPubMedCentralGoogle Scholar
  156. Sasabe, J., Suzuki, M., Miyoshi, Y., Tojo, Y., Okamura, C., Ito, S., Konno, R., Mita, M., Hamase, K., & Aiso, S. (2014). Ischemic acute kidney injury perturbs homeostasis of serine enantiomers in the body fluid in mice: Early detection of renal dysfunction using the ratio of serine enantiomers. PLoS One, 9, e86504.PubMedPubMedCentralCrossRefGoogle Scholar
  157. Sauer, R. T., Bolon, D. N., Burton, B. M., Burton, R. E., Flynn, J. M., Grant, R. A., Hersch, G. L., Joshi, S. A., Kenniston, J. A., Levchenko, I., Neher, S. B., Oakes, E. S., Siddiqui, S. M., Wah, D. A., & Baker, T. A. (2004). Sculpting the proteome with AAA(+) proteases and disassembly machines. Cell, 119, 9–18.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Schäffler, H., & Breitrück, A. (2018). From colonization to infection. Frontiers in Microbiology, 9, 646.PubMedPubMedCentralCrossRefGoogle Scholar
  159. Schmidt, N. W., Deshayes, S., Hawker, S., Blacker, A., Kasko, A. M., & Wong, G. C. (2014). Engineering persister-specific antibiotics with synergistic antimicrobial functions. ACS Nano, 8, 8786–8793.PubMedPubMedCentralCrossRefGoogle Scholar
  160. Schooling, S. R., & Beveridge, T. J. (2006). Membrane vesicles: An overlooked component of the matrices of biofilms. Journal of Bacteriology, 188, 5945–5957.PubMedPubMedCentralCrossRefGoogle Scholar
  161. Schweder, T., Lee, K. H., Lomovskaya, O., & Matin, A. (1996). Regulation of Escherichia coli starvation sigma factor (sigma s) by ClpXP protease. Journal of Bacteriology, 178, 470–476.Google Scholar
  162. Shah, D., Zhang, Z., Khodursky, A., Kaldalu, N., Kurg, K., & Lewis, K. (2006). Persisters: A distinct physiological state of E. coli. BMC Microbiology, 6, 53.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 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
  164. Sharma, B., Brown, A. V., Matluck, N. E., Hu, L. T., & Lewis, K. (2015). Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells. Antimicrobial Agents and Chemotherapy, 59, 4616–4624.PubMedPubMedCentralCrossRefGoogle Scholar
  165. Shi, W., Zhang, X., Jiang, X., Yuan, H., Lee, J. S., Barry, C. E., Wang, H., Zhang, W., & Zhang, Y. (2011). Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science, 333, 1630–1632.PubMedPubMedCentralCrossRefGoogle Scholar
  166. Siegele, D. A., & Kolter, R. (1992). Life after log. Journal of Bacteriology, 174, 345–348.PubMedPubMedCentralCrossRefGoogle Scholar
  167. Silverman, J. A., Perlmutter, N. G., & Shapiro, H. M. (2003). Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 47, 2538–2544.PubMedPubMedCentralCrossRefGoogle Scholar
  168. Slepenkov, S. V., & Witt, S. N. (2002). The unfolding story of the Escherichia coli Hsp70 DnaK: Is Dnak a holdase or an unfoldase? Molecular Microbiology, 45, 1197–1206.PubMedCrossRefPubMedCentralGoogle Scholar
  169. Spira, B., Silberstein, N., & Yagil, E. (1995). Guanosine 3′,5′-Bispyrophosphate (ppGpp) synthesis in cells of Escherichia coli starved for Pi. Journal of Bacteriology, 177, 4053–4058.Google Scholar
  170. Spoering, A. L., & Lewis, K. (2001). Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. Journal of Bacteriology, 183, 6746–6751.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 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
  172. Sprenger, M., Kasper, L., Hensel, M., & Hube, B. (2017). Metabolic adaptation of intracellular bacteria and fungi to macrophages. International Journal of Medical Microbiology, 308(1), 215–227.PubMedCrossRefPubMedCentralGoogle Scholar
  173. Stark, M., Liu, L. P., & Deber, C. M. (2002). Cationic hydrophobic peptides with antimicrobial activity. Antimicrobial Agents and Chemotherapy, 46, 3585–3590.PubMedPubMedCentralCrossRefGoogle Scholar
  174. Stephanopoulos, G. N., Aristidou, A. A., & Nielsen, J. (1998). Metabolic engineering: Principles and methodologies (pp. 119–120). San Diego: Academic.Google Scholar
  175. Stewart, P. S. (1996). Theoretical aspects of antibiotic diffusion into microbial biofilms. Antimicrobial Agents and Chemotherapy, 40, 2517–2522.PubMedPubMedCentralCrossRefGoogle Scholar
  176. Stewart, P. S. (2003). Diffusion in biofilms. Journal of Bacteriology, 185, 1485–1491.PubMedPubMedCentralCrossRefGoogle Scholar
  177. Stewart, P. S., & Franklin, M. J. (2008). Physiological heterogeneity in biofilms. Nature Reviews. Microbiology, 6, 199–210.PubMedCrossRefGoogle Scholar
  178. Stewart, P. S., Zhang, T., Xu, R., Pitts, B., Walters, M. C., Roe, F., Kikhney, J., & Moter, A. (2016). Reaction-diffusion theory explains hypoxia and heterogeneous growth within microbial biofilms associated with chronic infections. NPJ Biofilms Microbiomes, 2, 16012.PubMedPubMedCentralCrossRefGoogle Scholar
  179. Stoodley, P., Sauer, K., Davies, D. G., & Costerton, J. W. (2002). Biofilms as complex differentiated communities. Annual Review of Microbiology, 56, 187–209.PubMedCrossRefGoogle Scholar
  180. Sukheja, P., Kumar, P., Mittal, N., Li, S. G., Singleton, E., Russo, R., Perryman, A. L., Shrestha, R., Awasthi, D., Husain, S., Soteropoulos, P., Brukh, R., Connell, N., Freundlich, J. S., & Alland, D. (2017). A novel small-molecule inhibitor of the Mycobacterium tuberculosis demethylmenaquinone methyltransferase MenG is bactericidal to both growing and nutritionally deprived persister cells. Mbio, 8, e02022-16.PubMedPubMedCentralCrossRefGoogle Scholar
  181. Taber, H. W., Mueller, J. P., Miller, P. F., & Arrow, A. S. (1987). Bacterial uptake of aminoglycoside antibiotics. Microbiological Reviews, 51, 439–457.PubMedPubMedCentralGoogle Scholar
  182. Takikawa, O., Yoshida, R., Kido, R., & Hayaishi, O. (1986). Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. The Journal of Biological Chemistry, 261, 3648–3653.PubMedGoogle Scholar
  183. 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.Google Scholar
  184. Traxler, M. F., Summers, S. M., Nguyen, H. T., Zacharia, V. M., Hightower, G. A., Smith, J. T., & Conway, T. (2008). The global, ppGpp-mediated stringent response to amino acid starvation in Escherichia coli. Molecular Microbiology, 68, 1128–1148.PubMedPubMedCentralCrossRefGoogle Scholar
  185. Tuomanen, E., Cozens, R., Tosch, W., Zak, O., & Tomasz, A. (1986). The rate of killing of Escherichia coli by beta-lactam antibiotics is strictly proportional to the rate of bacterial growth. Journal of General Microbiology, 132, 1297–1304.PubMedPubMedCentralGoogle Scholar
  186. Ueta, M., Ohniwa, R. L., Yoshida, H., Maki, Y., Wada, C., & Wada, A. (2008). Role of HPF (hibernation promoting factor) in translational activity in Escherichia coli. Journal of Biochemistry, 143, 425–433.PubMedCrossRefGoogle Scholar
  187. 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.CrossRefGoogle Scholar
  188. 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.CrossRefGoogle Scholar
  189. Via, L. E., Savic, R., Weiner, D. M., Zimmerman, M. D., Prideaux, B., Irwin, S. M., Lyon, E., O’brien, P., Gopal, P., Eum, S., Lee, M., Lanoix, J. P., Dutta, N. K., Shim, T., Cho, J. S., Kim, W., Karakousis, P. C., Lenaerts, A., Nuermberger, E., Barry, C. E., & Dartois, V. (2015). Host-mediated bioactivation of pyrazinamide: Implications for efficacy, resistance, and therapeutic alternatives. ACS Infectious Diseases, 1, 203–214.PubMedPubMedCentralCrossRefGoogle Scholar
  190. Volzing, 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
  191. Wada, A., Yamazaki, Y., Fujita, N., & Ishihama, A. (1990). Structure and probable genetic location of a “ribosome modulation factor” associated with 100s ribosomes in stationary-phase Escherichia coli cells. Proceedings of the National Academy of Sciences of the United States of America, 87, 2657–2661.PubMedPubMedCentralCrossRefGoogle Scholar
  192. Wada, A., Igarashi, K., Yoshimura, S., Aimoto, S., & Ishihama, A. (1995). Ribosome modulation factor: Stationary growth phase-specific inhibitor of ribosome functions from Escherichia coli. Biochemical and Biophysical Research Communications, 214, 410–417.PubMedCrossRefGoogle Scholar
  193. Wade, M. M., & Zhang, Y. (2006). Effects of weak acids, UV and proton motive force inhibitors on pyrazinamide activity against Mycobacterium tuberculosis in vitro. The Journal of Antimicrobial Chemotherapy, 58, 936–941.PubMedCrossRefGoogle Scholar
  194. Walsh, C. (2003). Where will new antibiotics come from? Nature Reviews. Microbiology, 1, 65–70.PubMedCrossRefGoogle Scholar
  195. Walsh, C. T., & Wencewicz, T. A. (2014). Prospects for new antibiotics: A molecule-centered perspective. Journal of Antibiotics (Tokyo), 67, 7–22.CrossRefGoogle Scholar
  196. Walters, M. C., 3rd, Roe, F., Bugnicourt, A., Franklin, M. J., & Stewart, P. S. (2003). Contributions of antibiotic penetration, oxygen limitation, and low metabolic activity to tolerance of Pseudomonas aeruginosa biofilms to ciprofloxacin and tobramycin. Antimicrobial Agents and Chemotherapy, 47, 317–323.PubMedPubMedCentralCrossRefGoogle Scholar
  197. Wassarman, K. M., & Saecker, R. M. (2006). Synthesis-mediated release of a small RNA inhibitor of RNA polymerase. Science, 314, 1601–1603.PubMedCrossRefGoogle Scholar
  198. Watson, S. P., Clements, M. O., & Foster, S. J. (1998). Characterization of the starvation-survival response of Staphylococcus aureus. Journal of Bacteriology, 180, 1750–1758.PubMedPubMedCentralGoogle Scholar
  199. Weichart, D., Querfurth, N., Dreger, M., & Hengge-Aronis, R. (2003). Global role for ClpP-containing proteases in stationary-phase adaptation of Escherichia coli. Journal of Bacteriology, 185, 115–125.PubMedPubMedCentralCrossRefGoogle Scholar
  200. Wenthzel, A. M., Stancek, M., & Isaksson, L. A. (1998). Growth phase dependent stop codon readthrough and shift of translation reading frame in Escherichia coli. FEBS Letters, 421, 237–242.PubMedCrossRefPubMedCentralGoogle Scholar
  201. Wieland, H., Ullrich, S., Lang, F., & Neumeister, B. (2005). Intracellular multiplication of Legionella pneumophila depends on host cell amino acid transporter Slc1a5. Molecular Microbiology, 55, 1528–1537.PubMedCrossRefPubMedCentralGoogle Scholar
  202. Wigle, T. J., Sexton, J. Z., Gromova, A. V., Hadimani, M. B., Hughes, M. A., Smith, G. R., Yeh, L. A., & Singleton, S. F. (2009). Inhibitors of RecA activity discovered by high-throughput screening: Cell-permeable small molecules attenuate the SOS response in Escherichia coli. Journal of Biomolecular Screening, 14, 1092–1101.Google Scholar
  203. Wilson, K. H., & Perini, F. (1988). Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora. Infection and Immunity, 56, 2610–2614.PubMedPubMedCentralGoogle Scholar
  204. Wolf, S. G., Frenkiel, D., Arad, T., Finkel, S. E., Kolter, R., & Minsky, A. (1999). DNA protection by stress-induced biocrystallization. Nature, 400, 83–85.PubMedCrossRefPubMedCentralGoogle Scholar
  205. Wolff, J. A., Macgregor, C. H., Eisenberg, R. C., & Phibbs, P. V., Jr. (1991). Isolation and characterization of catabolite repression control mutants of Pseudomonas aeruginosa PAO. Journal of Bacteriology, 173, 4700–4706.PubMedPubMedCentralCrossRefGoogle Scholar
  206. Xiao, H., Kalman, M., Ikehara, K., Zemel, S., Glaser, G., & Cashel, M. (1991). Residual guanosine 3′,5′-bispyrophosphate synthetic activity of rela null mutants can be eliminated by spot null mutations. The Journal of Biological Chemistry, 266, 5980–5990.PubMedPubMedCentralGoogle Scholar
  207. Xu, K. D., Stewart, P. S., Xia, F., Huang, C. T., & Mcfeters, G. A. (1998). Spatial physiological heterogeneity in Pseudomonas aeruginosa biofilm is determined by oxygen availability. Applied and Environmental Microbiology, 64, 4035–4039.PubMedPubMedCentralGoogle Scholar
  208. Yakimov, A., Pobegalov, G., Bakhlanova, I., Khodorkovskii, M., Petukhov, M., & Baitin, D. (2017). Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide. Nucleic Acids Research, 45, 9788–9796.PubMedPubMedCentralCrossRefGoogle Scholar
  209. Yoshida, R., Imanishi, J., Oku, T., Kishida, T., & Hayaishi, O. (1981). Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proceedings of the National Academy of Sciences of the United States of America, 78, 129–132.PubMedPubMedCentralCrossRefGoogle Scholar
  210. Zhang, Y., Wade, M. M., Scorpio, A., Zhang, H., & Sun, Z. (2003). Mode of action of pyrazinamide: Disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. The Journal of Antimicrobial Chemotherapy, 52, 790–795.PubMedCrossRefPubMedCentralGoogle Scholar
  211. Zhang, S., Chen, J., Shi, W., Liu, W., Zhang, W., & Zhang, Y. (2013a). Mutations in panD encoding aspartate decarboxylase are associated with pyrazinamide resistance in Mycobacterium tuberculosis. Emerging Microbes and Infections, 2, e34.PubMedCrossRefPubMedCentralGoogle Scholar
  212. Zhang, Y., Shi, W., Zhang, W., & Mitchison, D. (2013b). Mechanisms of pyrazinamide action and resistance. Microbiology Spectrum, 2, 1–12.PubMedPubMedCentralGoogle Scholar
  213. Zimhony, O., Cox, J. S., Welch, J. T., Vilchèze, C., & Jacobs, W. R. (2000). Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nature Medicine, 6, 1043–1047.PubMedCrossRefPubMedCentralGoogle Scholar
  214. Zogaj, X., Nimtz, M., Rohde, M., Bokranz, W., & Römling, U. (2001). The multicellular morphotypes of Salmonella typhimurium and Escherichia coli produce cellulose as the second component of the extracellular matrix. Molecular Microbiology, 39, 1452–1463.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Chemical and Biological EngineeringPrinceton UniversityPrincetonUSA
  2. 2.Department of Molecular Biology and BiophysicsUConn HealthFarmingtonUSA

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