Skip to main content

Nutrient Depletion and Bacterial Persistence

  • Chapter
  • First Online:
Persister Cells and Infectious Disease

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allison, K. R., Brynildsen, M. P., & Collins, J. J. (2011). Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature, 473, 216–220.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Amato, S. M., Orman, M. A., & Brynildsen, M. P. (2013). Metabolic control of persister formation in Escherichia coli. Molecular Cell, 50, 475–487.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Appelberg, R. (2006). Macrophage nutriprive antimicrobial mechanisms. Journal of Leukocyte Biology, 79, 1117–1128.

    Article  CAS  PubMed  Google Scholar 

  • Armstrong, E. S., & Miller, G. H. (2010). Combating evolution with intelligent design: The neoglycoside ACHN-490. Current Opinion in Microbiology, 13, 565–573.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bahar, A. A., & Ren, D. (2013). Antimicrobial peptides. Pharmaceuticals (Basel), 6, 1543–1575.

    Article  CAS  Google Scholar 

  • Balaban, N. Q. (2011). Persistence: Mechanisms for triggering and enhancing phenotypic variability. Current Opinion in Genetics & Development, 21, 768–775.

    Article  CAS  Google Scholar 

  • Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., & Leibler, S. (2004). Bacterial persistence as a phenotypic switch. Science, 305, 1622–1625.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Beisel, W. R. (1975). Metabolic response to infection. Annual Review of Medicine, 26, 9–20.

    Article  CAS  PubMed  Google Scholar 

  • Belkaid, Y., & Segre, J. A. (2014). Dialogue between skin microbiota and immunity. Science, 346, 954–959.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Blaser, M. J., & Falkow, S. (2009). What are the consequences of the disappearing human microbiota? Nature Reviews. Microbiology, 7, 887–894.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Brooks, T., & Keevil, C. W. (1997). A simple artificial urine for the growth of urinary pathogens. Letters in Applied Microbiology, 24, 203–206.

    Article  CAS  PubMed  Google Scholar 

  • Brown, S. A., Palmer, K. L., & Whiteley, M. (2008). Revisiting the host as a growth medium. Nature Reviews. Microbiology, 6, 657–666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Culp, E., & Wright, G. D. (2017). Bacterial proteases, untapped antimicrobial drug targets. Journal of Antibiotics (Tokyo), 70, 366–377.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis, B. D. (1987). Mechanism of bactericidal action of aminoglycosides. Microbiological Reviews, 51, 341–350.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drlica, K., & Zhao, X. (1997). DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiology and Molecular Biology Review, 61, 377–392.

    CAS  Google Scholar 

  • Drlica, K., Malik, M., Kerns, R. J., & Zhao, X. (2008). Quinolone-mediated bacterial death. Antimicrobial Agents and Chemotherapy, 52, 385–392.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Ehlers, S., & Schaible, U. E. (2012). The granuloma in tuberculosis: Dynamics of a host-pathogen collusion. Frontiers in Immunology, 3, 411.

    PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Finkel, S. E. (2006). Long-term survival during stationary phase: Evolution and the GASP phenotype. Nature Reviews. Microbiology, 4, 113–120.

    Article  CAS  PubMed  Google Scholar 

  • Flemming, H. C., & Wingender, J. (2010). The biofilm matrix. Nature Reviews. Microbiology, 8, 623–633.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Freyberg, Z., & Harvill, E. T. (2017). Pathogen manipulation of host metabolism: A common strategy for immune evasion. PLoS Pathogens, 13, e1006669.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Gefen, O., & Balaban, N. Q. (2009). The importance of being persistent: Heterogeneity of bacterial populations under antibiotic stress. FEMS Microbiology Reviews, 33, 704–717.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Gengenbacher, M., & Kaufmann, S. H. (2012). Mycobacterium tuberculosis: Success through dormancy. FEMS Microbiology Reviews, 36, 514–532.

    Article  CAS  PubMed  Google Scholar 

  • Gold, B., & Nathan, C. (2017). Targeting phenotypically tolerant Mycobacterium tuberculosis. Microbiology Spectrum, 5. https://doi.org/10.1128/microbiolspec

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Gottesman, S., & Maurizi, M. R. (2001). Cell biology. Surviving starvation. Science, 293, 614–615.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Hall-Stoodley, L., Costerton, J. W., & Stoodley, P. (2004). Bacterial biofilms: From the natural environment to infectious diseases. Nature Reviews. Microbiology, 2, 95–108.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu, Y., & Coates, A. (2012). Nonmultiplying bacteria are profoundly tolerant to antibiotics. Handbook of experimental pharmacology, 99–119.

    Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Kamada, N., Chen, G. Y., Inohara, N., & Núñez, G. (2013). Control of pathogens and pathobionts by the gut microbiota. Nature Immunology, 14, 685–690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keren, I., Kaldalu, N., Spoering, A., Wang, Y., & Lewis, K. (2004). Persister cells and tolerance to antimicrobials. FEMS Microbiology Letters, 230, 13–18.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lange, R., & Hengge-Aronis, R. (1991). Identification of a central regulator of stationary-phase gene expression in Escherichia coli. Molecular Microbiology, 5, 49–59.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, K. (2007). Persister cells, dormancy and infectious disease. Nature Reviews. Microbiology, 5, 48–56.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, K. (2010). Persister cells. Annual Review of Microbiology, 64, 357–372.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Mandelstam, J. (1963). Protein turnover and its function in economy of cell. Annals of the New York Academy of Sciences, 102, 621–636.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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 

  • Meylan, S., Andrews, I. W., & Collins, J. J. (2018). Targeting antibiotic tolerance, pathogen by pathogen. Cell, 172, 1228–1238.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Mulcahy, L. R., Isabella, V. M., & Lewis, K. (2014). Pseudomonas aeruginosa biofilms in disease. Microbial Ecology, 68, 1–12.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nair, S., & Finkel, S. E. (2004). Dps protects cells against multiple stresses during stationary phase. Journal of Bacteriology, 186, 4192–4198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Nystrom, T. (2004). Stationary-phase physiology. Annual Review of Microbiology, 58, 161–181.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Olsen, I. (2005). New principles in ecological regulation—Features from the oral cavity. Microbial Ecology in Health and Disease, 18, 26–31.

    Article  Google Scholar 

  • Orman, M. A., & Brynildsen, M. P. (2015). Inhibition of stationary phase respiration impairs persister formation in E. coli. Nature Communications, 6, 7983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Passalacqua, K. D., Charbonneau, M. E., & O’riordan, M. X. (2016). Bacterial metabolism shapes the host-pathogen interface. Microbiology Spectrum, 4. https://doi.org/10.1128/microbiolspec.VMBF-0027-2015

  • 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.

    Article  PubMed  Google Scholar 

  • Pereira, F. C., & Berry, D. (2017). Microbial nutrient niches in the gut. Environmental Microbiology, 19, 1366–1378.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potera, C. (1999). Forging a link between biofilms and disease. Science, 283(1837), 1839.

    Google Scholar 

  • Potrykus, K., & Cashel, M. (2008). (p)ppGpp: Still magical? Annual Review of Microbiology, 62, 35–51.

    Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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 

  • Radzikowski, J. L., Schramke, H., & Heinemann, M. (2017). Bacterial persistence from a system-level perspective. Current Opinion in Biotechnology, 46, 98–105.

    Article  CAS  PubMed  Google Scholar 

  • Rao, N. N., & Kornberg, A. (1996). Inorganic polyphosphate supports resistance and survival of stationary-phase Escherichia coli. Journal of Bacteriology, 178, 1394–1400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reitzer, L. (2003). Nitrogen assimilation and global regulation in Escherichia coli. Annual Review of Microbiology, 57, 155–176.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schäffler, H., & Breitrück, A. (2018). From colonization to infection. Frontiers in Microbiology, 9, 646.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schooling, S. R., & Beveridge, T. J. (2006). Membrane vesicles: An overlooked component of the matrices of biofilms. Journal of Bacteriology, 188, 5945–5957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegele, D. A., & Kolter, R. (1992). Life after log. Journal of Bacteriology, 174, 345–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Stark, M., Liu, L. P., & Deber, C. M. (2002). Cationic hydrophobic peptides with antimicrobial activity. Antimicrobial Agents and Chemotherapy, 46, 3585–3590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephanopoulos, G. N., Aristidou, A. A., & Nielsen, J. (1998). Metabolic engineering: Principles and methodologies (pp. 119–120). San Diego: Academic.

    Google Scholar 

  • Stewart, P. S. (1996). Theoretical aspects of antibiotic diffusion into microbial biofilms. Antimicrobial Agents and Chemotherapy, 40, 2517–2522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart, P. S. (2003). Diffusion in biofilms. Journal of Bacteriology, 185, 1485–1491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart, P. S., & Franklin, M. J. (2008). Physiological heterogeneity in biofilms. Nature Reviews. Microbiology, 6, 199–210.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Stoodley, P., Sauer, K., Davies, D. G., & Costerton, J. W. (2002). Biofilms as complex differentiated communities. Annual Review of Microbiology, 56, 187–209.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Taber, H. W., Mueller, J. P., Miller, P. F., & Arrow, A. S. (1987). Bacterial uptake of aminoglycoside antibiotics. Microbiological Reviews, 51, 439–457.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Walsh, C. (2003). Where will new antibiotics come from? Nature Reviews. Microbiology, 1, 65–70.

    Article  CAS  PubMed  Google Scholar 

  • Walsh, C. T., & Wencewicz, T. A. (2014). Prospects for new antibiotics: A molecule-centered perspective. Journal of Antibiotics (Tokyo), 67, 7–22.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wassarman, K. M., & Saecker, R. M. (2006). Synthesis-mediated release of a small RNA inhibitor of RNA polymerase. Science, 314, 1601–1603.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, Y., Shi, W., Zhang, W., & Mitchison, D. (2013b). Mechanisms of pyrazinamide action and resistance. Microbiology Spectrum, 2, 1–12.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wendy W. K. Mok or Mark P. Brynildsen .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mok, W.W.K., Brynildsen, M.P. (2019). Nutrient Depletion and Bacterial Persistence. In: Lewis, K. (eds) Persister Cells and Infectious Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-25241-0_6

Download citation

Publish with us

Policies and ethics