Key Points
-
Most bacteria in the environment are not actively growing most of the time, but the molecular mechanisms that govern growth-arrested states are not well understood.
-
Growth arrest has been studied by depleting nutrients or oxygen, which leads to large changes in metabolism, nucleoid state and the regulation of gene expression compared with exponential growth. Metabolism shifts during growth arrest to the use of alternative sources of energy and biosynthetic precursors, including internal stores.
-
The regulation of gene expression in non-growing states seems to differ from regulation during the entry to stationary phase and prioritizes successful expression of maintenance and survival functions.
-
The nucleoid is highly condensed during growth arrest through the activities of nucleoid-associated proteins, which not only protect DNA but also modulate gene expression.
-
Progress in understanding the physiology of stasis requires work to identify the key environmental factors that constrain microbial growth in situ, and, informed by this knowledge, laboratory studies that use emerging tools to reveal the molecular mechanisms that sustain cells through periods of growth arrest.
Abstract
Most bacteria spend the majority of their time in prolonged states of very low metabolic activity and little or no growth, in which electron donors, electron acceptors and/or nutrients are limited, but cells are poised to undergo rapid division cycles when resources become available. These non-growing states are far less studied than other growth states, which leaves many questions regarding basic bacterial physiology unanswered. In this Review, we discuss findings from a small but diverse set of systems that have been used to investigate how growth-arrested bacteria adjust metabolism, regulate transcription and translation, and maintain their chromosomes. We highlight major questions that remain to be addressed, and suggest that progress in answering them will be aided by recent methodological advances and by dialectic between environmental and molecular microbiology perspectives.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
De Nobili, M., Contin, M., Mondini, C. & Brookes, P. C. Soil microbial biomass is triggered into activity by trace amounts of substrate. Soil Biol. Biochem. 33, 1163–1170 (2001).
Amy, P. S. & Morita, R. Y. Starvation–survival patterns of sixteen freshly isolated open-ocean bacteria. Appl. Environ. Microbiol. 45, 1109–1115 (1983).
Schink, B. Energetics of syntrophic cooperation in methanogenic degradation. Microbiol. Mol. Biol. Rev. 61, 262–280 (1997).
Lever, M. A. et al. Life under extreme energy limitation: a synthesis of laboratory- and field-based investigations. FEMS Microbiol. Rev. 39, 688–728 (2015).
Kolter, R. Growth in studying the cessation of growth. J. Bacteriol. 181, 697–699 (1999).
Finkel, S. E. Long-term survival during stationary phase: evolution and the GASP phenotype. Nat. Rev. Microbiol. 4, 113–120 (2006).
Notley-McRobb, L., King, T. & Ferenci, T. rpoS mutations and loss of general stress resistance in Escherichia coli populations as a consequence of conflict between competing stress responses. J. Bacteriol. 184, 806–811 (2002).
Gefen, O., Fridman, O., Ronin, I. & Balaban, N. Q. Direct observation of single stationary-phase bacteria reveals a surprisingly long period of constant protein production activity. Proc. Natl Acad. Sci. USA 111, 556–561 (2014). This study is notable because it provides insight into behaviours at a single-cell level in a stationary phase-like non-growing condition, pointing the way forward for future research that takes into account the possibility for population heterogeneity.
Battesti, A., Majdalani, N. & Gottesman, S. The RpoS-mediated general stress response in Escherichia coli. Annu. Rev. Microbiol. 65, 189–213 (2011).
Nystrom, T. Stationary-phase physiology. Annu. Rev. Microbiol. 58, 161–181 (2004).
Higgins, D. & Dworkin, J. Recent progress in Bacillus subtilis sporulation. FEMS Microbiol. Rev. 36, 131–148 (2012).
Nystrom, T. & Gustavsson, N. Maintenance energy requirement: what is required for stasis survival of Escherichia coli? Biochim. Biophys. Acta. 1365, 225–231 (1998).
Koch, A. L. Microbial physiology and ecology of slow growth. Microbiol. Mol. Biol. Rev. 61, 305–318 (1997).
Harold, F. M. Conservation and transformation of energy by bacterial membranes. Bacteriol. Rev. 36, 172–230 (1972).
Farewell, A., Diez, A. A., DiRusso, C. D. & Nystrom, T. Role of the Escherichia coli FadR regulator in stasis survival and growth phase-dependent expression of the uspA. fad, and fab genes. J. Bacteriol. 178, 6443–6450 (1996).
Hood, M. A., Guckert, J. B., White, D. C. & Deck, F. Effect of nutrient deprivation on lipid, carbohydrate, DNA, RNA, and protein levels in Vibrio cholerae. Appl. Environ. Microbiol. 52, 788–793 (1986).
Kaberdin, V. R. et al. Unveiling the metabolic pathways associated with the adaptive reduction of cell size during Vibrio harveyi persistence in seawater microcosms. Microb. Ecol. 70, 689–700 (2015).
Geesey, G. G. & Morita, R. Y. Capture of arginine at low concentrations by a marine psychrophilic bacterium. Appl. Environ. Microbiol. 38, 1092–1097 (1979).
Zimmer, D. P. et al. Nitrogen regulatory protein C-controlled genes of Escherichia coli: scavenging as a defense against nitrogen limitation. Proc. Natl Acad. Sci. USA 97, 14674–14679 (2000).
van der Ploeg, J., Eichhorn, E. & Leisinger, T. Sulfonate–sulfur metabolism and its regulation in Escherichia coli. Arch. Microbiol. 176, 1–8 (2001).
Ishige, T., Krause, M., Bott, M., Wendisch, V. F. & Sahm, H. The phosphate starvation stimulon of Corynebacterium glutamicum determined by DNA microarray analyses. J. Bacteriol. 185, 4519–4529 (2003).
Zambrano, M. M., Siegele, D. A., Almirón, M., Tormo, A. & Kolter, R. Microbial competition: Escherichia coli mutants that take over stationary phase cultures. Science 259, 1757–1760 (1993).
Zinser, E. R. & Kolter, R. Mutations enhancing amino acid catabolism confer a growth advantage in stationary phase. J. Bacteriol. 181, 5800–5807 (1999).
Zinser, E. R. & Kolter, R. Prolonged stationary-phase incubation selects for lrp mutations in Escherichia coli K-12. J. Bacteriol. 182, 4361–4365 (2000).
Cowley, E. S., Kopf, S. H., LaRiviere, A., Ziebis, W. & Newman, D. K. Pediatric cystic fibrosis sputum can be chemically dynamic, anoxic, and extremely reduced due to hydrogen sulfide formation. mBio 6, e00767 (2015).
Rao, S. P., Alonso, S., Rand, L., Dick, T. & Pethe, K. The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 105, 11945–11950 (2008).
Watanabe, S. et al. Fumarate reductase activity maintains an energized membrane in anaerobic Mycobacterium tuberculosis. PLoS Pathog. 7, e1002287 (2011). This work comprehensively and quantitatively describes the metabolism of M. tuberculosis during hypoxia.
Eoh, H. & Rhee, K. Y. Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 110, 6554–6559 (2013).
Zimmermann, M. et al. Dynamic exometabolome analysis reveals active metabolic pathways in non-replicating mycobacteria. Environ. Microbiol. 17, 4802–4815 (2015).
Wayne, L. G. & Sohaskey, C. D. Nonreplicating persistence of Mycobacterium tuberculosis. Annu. Rev. Microbiol. 55, 139–163 (2001).
Leistikow, R. L. et al. The Mycobacterium tuberculosis DosR regulon assists in metabolic homeostasis and enables rapid recovery from nonrespiring dormancy. J. Bacteriol. 192, 1662–1670 (2010).
Glasser, N. R., Kern, S. E. & Newman, D. K. Phenazine redox cycling enhances anaerobic survival in Pseudomonas aeruginosa by facilitating generation of ATP and a proton-motive force. Mol. Microbiol. 92, 399–412 (2014). In this study, the authors analyse several metabolic strategies that are used by P. aeruginosa during anaerobic survival, which provides useful background information for understanding metabolic constraints in this state.
Eschbach, M. et al. Long-term anaerobic survival of the opportunistic pathogen Pseudomonas aeruginosa via pyruvate fermentation. J. Bacteriol. 186, 4596–4604 (2004).
Vander Wauven, C., Pierard, A., Kley-Raymann, M. & Haas, D. Pseudomonas aeruginosa mutants affected in anaerobic growth on arginine: evidence for a four-gene cluster encoding the arginine deiminase pathway. J. Bacteriol. 160, 928–934 (1984).
Schuetz, R., Zamboni, N., Zampieri, M., Heinemann, M. & Sauer, U. Multidimensional optimality of microbial metabolism. Science 336, 601–604 (2012).
Foster, K. R. & Bell, T. Competition, not cooperation, dominates interactions among culturable microbial species. Curr. Biol. 22, 1845–1850 (2012).
Bryant, M. P., Wolin, E. A., Wolin, M. J. & Wolfe, R. S. Methanobacillus omelianskii, a symbiotic association of two species of bacteria. Arch. Mikrobiol. 59, 20–31 (1967).
Venkataraman, A., Rosenbaum, M. A., Perkins, S. D., Werner, J. J. & Angenent, L. T. Metabolite-based mutualism between Pseudomonas aeruginosa PA14 and Enterobacter aerogenes enhances current generation in bioelectrochemical systems. Energy Environ. Sci. 4, 4550 (2011).
Dennis, P. P., Ehrenberg, M. & Bremer, H. Control of rRNA synthesis in Escherichia coli: a systems biology approach. Microbiol. Mol. Biol. Rev. 68, 639–668 (2004).
Subramaniam, A. R., Zid, B. M. & O'Shea, E. K. An integrated approach reveals regulatory controls on bacterial translation elongation. Cell 159, 1200–1211 (2014).
Potrykus, K. & Cashel, M. (p)ppGpp: still magical? Annu. Rev. Microbiol. 62, 35–51 (2008).
Typas, A., Becker, G. & Hengge, R. The molecular basis of selective promoter activation by the σS subunit of RNA polymerase. Mol. Microbiol. 63, 1296–1306 (2007).
Perederina, A. et al. Regulation through the secondary channel — structural framework for ppGpp–DksA synergism during transcription. Cell 118, 297–309 (2004).
Paul, B. J. et al. DksA: a critical component of the transcription initiation machinery that potentiates the regulation of rRNA promoters by ppGpp and the initiating NTP. Cell 118, 311–322 (2004).
Perron, K., Comte, R. & van Delden, C. DksA represses ribosomal gene transcription in Pseudomonas aeruginosa by interacting with RNA polymerase on ribosomal promoters. Mol. Microbiol. 56, 1087–1102 (2005).
Murray, H. D., Schneider, D. A. & Gourse, R. L. Control of rRNA expression by small molecules is dynamic and nonredundant. Mol. Cell 12, 125–134 (2003).
Perez-Osorio, A. C., Williamson, K. S. & Franklin, M. J. Heterogeneous rpoS and rhlR mRNA levels and 16S rRNA/rDNA (rRNA gene) ratios within Pseudomonas aeruginosa biofilms, sampled by laser capture microdissection. J. Bacteriol. 192, 2991–3000 (2010).
Babin, B. M. et al. SutA is a bacterial transcription factor expressed during slow growth in Pseudomonas aeruginosa. Proc. Natl Acad. Sci. USA 113, E597–E605 (2016). This work takes advantage of time-specific proteome labelling to determine which proteins are preferentially expressed during anaerobic survival in P. aeruginosa. Such preferential expression helps to circumvent the problem of having low levels of new protein synthesis in this condition.
Farrell, M. J. & Finkel, S. E. The growth advantage in stationary-phase phenotype conferred by rpoS mutations is dependent on the pH and nutrient environment. J. Bacteriol. 185, 7044–7052 (2003).
Peterson, C. N., Levchenko, I., Rabinowitz, J. D., Baker, T. A. & Silhavy, T. J. RpoS proteolysis is controlled directly by ATP levels in Escherichia coli. Genes Dev. 26, 548–553 (2012).
Mika, F. & Hengge, R. A two-component phosphotransfer network involving ArcB, ArcA, and RssB coordinates synthesis and proteolysis of σS (RpoS) in E. coli. Genes Dev. 19, 2770–2781 (2005).
Battesti, A., Majdalani, N. & Gottesman, S. Stress sigma factor RpoS degradation and translation are sensitive to the state of central metabolism. Proc. Natl Acad. Sci. USA 112, 5159–5164 (2015).
Chapman, A. G., Fall, L. & Atkinson, D. E. Adenylate energy charge in Escherichia coli during growth and starvation. J. Bacteriol. 108, 1072–1086 (1971).
Zhang, Y. et al. DksA guards elongating RNA polymerase against ribosome-stalling-induced arrest. Mol. Cell 53, 766–778 (2014).
Belogurov, G. A. & Artsimovitch, I. Regulation of transcript elongation. Annu. Rev. Microbiol. 69, 49–69 (2015).
Starosta, A. L., Lassak, J., Jung, K. & Wilson, D. N. The bacterial translation stress response. FEMS Microbiol. Rev. 38, 1172–1201 (2014).
Wassarman, K. M. & Saecker, R. M. Synthesis-mediated release of a small RNA inhibitor of RNA polymerase. Science 314, 1601–1603 (2006).
Kline, B. C., McKay, S. L., Tang, W. W. & Portnoy, D. A. The Listeria monocytogenes hibernation-promoting factor is required for the formation of 100S ribosomes, optimal fitness, and pathogenesis. J. Bacteriol. 197, 581–591 (2015).
Deutscher, M. P. Degradation of stable RNA in bacteria. J. Biol. Chem. 278, 45041–45044 (2003).
Zundel, M. A., Basturea, G. N. & Deutscher, M. P. Initiation of ribosome degradation during starvation in Escherichia coli. RNA 15, 977–983 (2009).
Hauser, R. et al. RsfA (YbeB) proteins are conserved ribosomal silencing factors. PLoS Genet. 8, e1002815 (2012).
Stallings, C. L. et al. CarD is an essential regulator of rRNA transcription required for Mycobacterium tuberculosis persistence. Cell 138, 146–159 (2009).
Srivastava, D. B. et al. Structure and function of CarD, an essential mycobacterial transcription factor. Proc. Natl Acad. Sci. USA 110, 12619–12624 (2013).
Burmann, B. M. et al. A NusE–NusG complex links transcription and translation. Science 328, 501–504 (2010).
Kusuya, Y., Kurokawa, K., Ishikawa, S., Ogasawara, N. & Oshima, T. Transcription factor GreA contributes to resolving promoter-proximal pausing of RNA polymerase in Bacillus subtilis cells. J. Bacteriol. 193, 3090–3099 (2011).
Hersch, S. J. et al. Divergent protein motifs direct elongation factor P-mediated translational regulation in Salmonella enterica and Escherichia coli. mBio 4, e00180-13 (2013).
Wolf, S. G. et al. DNA protection by stress-induced biocrystallization. Nature 400, 83–85 (1999).
Wang, J. D. & Levin, P. A. Metabolism, cell growth and the bacterial cell cycle. Nat. Rev. Microbiol. 7, 822–827 (2009).
Skarstad, K. & Katayama, T. Regulating DNA replication in bacteria. Cold Spring Harb. Perspect. Biol. 5, a012922 (2013).
Hill, N. S., Buske, P. J., Shi, Y. & Levin, P. A. A moonlighting enzyme links Escherichia coli cell size with central metabolism. PLoS Genet. 9, e1003663 (2013). This work provides mechanistic insight into how the regulation of metabolism and cell division can be coordinated.
Chai, Q. et al. Organization of ribosomes and nucleoids in Escherichia coli cells during growth and in quiescence. J. Biol. Chem. 289, 11342–11352 (2014).
Stracy, M. et al. Live-cell superresolution microscopy reveals the organization of RNA polymerase in the bacterial nucleoid. Proc. Natl Acad. Sci. USA 112, E4390–E4399 (2015).
Dillon, S. C. & Dorman, C. J. Bacterial nucleoid-associated proteins, nucleoid structure and gene expression. Nat. Rev. Microbiol. 8, 185–195 (2010).
Koch, C. & Kahmann, R. Purification and properties of the Escherichia coli host factor required for inversion of the G segment in bacteriophage Mu. J. Biol. Chem. 261, 15673–15678 (1986).
Mallik, P. et al. Growth phase-dependent regulation and stringent control of fis are conserved processes in enteric bacteria and involve a single promoter (fis P) in Escherichia coli. J. Bacteriol. 186, 122–135 (2003).
Nair, S. & Finkel, S. E. Dps protects cells against multiple stresses during stationary phase. J. Bacteriol. 186, 4192–4198 (2004).
Grainger, D. C., Goldberg, M. D., Lee, D. J. & Busby, S. J. Selective repression by Fis and H-NS at the Escherichia coli dps promoter. Mol. Microbiol. 68, 1366–1377 (2008).
Ceci, P. et al. DNA condensation and self-aggregation of Escherichia coli Dps are coupled phenomena related to the properties of the N-terminus. Nucleic Acids Res. 32, 5935–5944 (2004).
Frenkiel-Krispin, D. et al. Nucleoid restructuring in stationary-state bacteria. Mol. Microbiol. 51, 395–405 (2004).
Kim, J. et al. Fundamental structural units of the Escherichia coli nucleoid revealed by atomic force microscopy. Nucleic Acids Res. 32, 1982–1992 (2004).
Karas, V. O., Westerlaken, I. & Meyer, A. S. The DNA-binding protein from starved cells (Dps) utilizes dual functions to defend cells against multiple stresses. J. Bacteriol. 197, 3206–3215 (2015).
Grant, R. A., Filman, D. J., Finkel, S. E., Kolter, R. & Hogle, J. M. The crystal structure of Dps, a ferritin homolog that binds and protects DNA. Nat. Struct. Biol. 5, 294–303 (1998).
Corzett, C. H., Goodman, M. F. & Finkel, S. E. Competitive fitness during feast and famine: how SOS DNA polymerases influence physiology and evolution in Escherichia coli. Genetics 194, 409–420 (2013).
Asakura, H. et al. Gene expression profile of Vibrio cholerae in the cold stress-induced viable but non-culturable state. Environ. Microbiol. 9, 869–879 (2007).
Lee, S. Y., Lim, C. J., Droge, P. & Yan, J. Regulation of bacterial DNA packaging in early stationary phase by competitive DNA binding of Dps and IHF. Sci. Rep. 5, 18146 (2015).
Landgraf, J. R., Wu, J. & Calvo, J. M. Effects of nutrition and growth rate on Lrp levels in Escherichia coli. J. Bacteriol. 178, 6930–6936 (1996).
Moore, J. M. et al. Roles of nucleoid-associated proteins in stress-induced mutagenic break repair in starving Escherichia coli. Genetics 201, 1349–1362 (2015).
Morikawa, K. et al. Bacterial nucleoid dynamics: oxidative stress response in Staphylococcus aureus. Genes Cells 11, 409–423 (2006).
Finkel, S. E. & Kolter, R. Evolution of microbial diversity during prolonged starvation. Proc. Natl Acad. Sci. USA 96, 4023–4027 (1999). This work describes long-term stationary-phase incubations and the surprising finding that beneficial mutations can sweep populations even when population numbers are not increasing over time, giving rise to considerable additional study of the GASP phenotype.
Kondorosi, E., Mergaert, P. & Kereszt, A. A paradigm for endosymbiotic life: cell differentiation of Rhizobium bacteria provoked by host plant factors. Annu. Rev. Microbiol. 67, 611–628 (2013).
Lyons, N. A. & Kolter, R. On the evolution of bacterial multicellularity. Curr. Opin. Microbiol. 24, 21–28 (2015).
Xu, H. S. et al. Survival and viability of nonculturable Escherichia coli and Vibrio cholerae in the estuarine and marine environment. Microb. Ecol. 8, 313–323 (1982).
Ayrapetyan, M., Williams, T. C. & Oliver, J. D. Bridging the gap between viable but non-culturable and antibiotic persistent bacteria. Trends Microbiol. 23, 7–13 (2015).
Ramamurthy, T., Ghosh, A., Pazhani, G. P. & Shinoda, S. Current perspectives on viable but non-culturable (VBNC) pathogenic bacteria. Front. Public Health 2, 103 (2014).
Epstein, S. S. The phenomenon of microbial uncultivability. Curr. Opin. Microbiol. 16, 636–642 (2013).
Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L. & Leibler, S. Bacterial persistence as a phenotypic switch. Science 305, 1622–1625 (2004). This work shows that non-growing states can be observed in growing populations, and that bacteria can enter and leave these states reversibly.
Kaspy, I. et al. HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase. Nat. Commun. 4, 3001 (2013).
Cohen, N. R., Lobritz, M. A. & Collins, J. J. Microbial persistence and the road to drug resistance. Cell Host Microbe 13, 632–642 (2013).
Rotem, E. et al. Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Proc. Natl Acad. Sci. USA 107, 12541–12546 (2010).
Williamson, K. S. et al. Heterogeneity in Pseudomonas aeruginosa biofilms includes expression of ribosome hibernation factors in the antibiotic-tolerant subpopulation and hypoxia-induced stress response in the metabolically active population. J. Bacteriol. 194, 2062–2073 (2012).
Liu, J. et al. Metabolic co-dependence gives rise to collective oscillations within biofilms. Nature 523, 550–554 (2015). This work suggests that transient non-growing states might contribute importantly to the function and fitness of biofilms, which, in our view, is a motivator for future study into how growth arrest might be regulated over relatively small spatial and temporal scales in natural microbial communities.
Lin, B., Westerhoff, H. V. & Roling, W. F. How Geobacteraceae may dominate subsurface biodegradation: physiology of Geobacter metallireducens in slow-growth habitat-simulating retentostats. Environ. Microbiol. 11, 2425–2433 (2009).
Landgraf, P., Antileo, E. R., Schuman, E. M. & Dieterich, D. C. BONCAT: metabolic labeling, click chemistry, and affinity purification of newly synthesized proteomes. Methods Mol. Biol. 1266, 199–215 (2015).
Jorth, P. et al. Regional isolation drives bacterial diversification within cystic fibrosis lungs. Cell Host Microbe 18, 307–319 (2015).
van Opijnen, T. & Camilli, A. Transposon insertion sequencing: a new tool for systems-level analysis of microorganisms. Nat. Rev. Microbiol. 11, 435–442 (2013).
Croucher, N. J. & Thomson, N. R. Studying bacterial transcriptomes using RNA-seq. Curr. Opin. Microbiol. 13, 619–624 (2010).
Myers, K. S., Park, D. M., Beauchene, N. A. & Kiley, P. J. Defining bacterial regulons using ChIP-seq. Methods 86, 80–88 (2015).
Ingolia, N. T. Genome-wide translational profiling by ribosome footprinting. Methods Enzymol. 470, 119–142 (2010).
Larson, M. H. et al. A pause sequence enriched at translation start sites drives transcription dynamics in vivo. Science 344, 1042–1047 (2014).
Singh, G., Ricci, E. P. & Moore, M. J. RIPiT-Seq: a high-throughput approach for footprinting RNA:protein complexes. Methods 65, 320–332 (2014).
Kopf, S. H. et al. Trace incorporation of heavy water reveals slow and heterogeneous pathogen growth rates in cystic fibrosis sputum. Proc. Natl Acad. Sci. USA 113, E110–E116 (2016). In this study, the authors apply sophisticated isotope labelling techniques borrowed from geochemistry to gain insight into very slow growth rates occurring in situ in a human infection context.
Radajewski, S., McDonald, I. R. & Murrell, J. C. Stable-isotope probing of nucleic acids: a window to the function of uncultured microorganisms. Curr. Opin. Biotechnol. 14, 296–302 (2003).
Jiang, C. Y. et al. High throughput single-cell cultivation on microfluidic streak plates. Appl. Environ. Microbiol. 82, 2210–2218 (2016).
Cannon, M. B. & Remington, S. J. Redox-sensitive green fluorescent protein: probes for dynamic intracellular redox responses. A review. Methods Mol. Biol. 476, 51–65 (2008).
Berg, J., Hung, Y. P. & Yellen, G. A genetically encoded fluorescent reporter of ATP:ADP ratio. Nat. Methods 6, 161–166 (2009).
Wagner, M., Nielsen, P. H., Loy, A., Nielsen, J. L. & Daims, H. Linking microbial community structure with function: fluorescence in situ hybridization-microautoradiography and isotope arrays. Curr. Opin. Biotechnol. 17, 83–91 (2006).
Huang, W. E. et al. Raman–FISH: combining stable-isotope Raman spectroscopy and fluorescence in situ hybridization for the single cell analysis of identity and function. Environ. Microbiol. 9, 1878–1889 (2007).
Acknowledgements
The authors dedicate this review to R. Kolter, on the occasion of his upcoming retirement. Whether in his pursuit of meaningful bacterial or human lifestyles, he has been ahead of the curve his entire career. The authors thank him for inspiration, and thank members in the laboratory of D.K.N, S. Finkel and P. Esra for helpful feedback on this manuscript. D.K.N. is an Investigator of the Howard Hughes Medical Institute (HHMI). The authors thank the HHMI and the US National Institutes of Health (NIH; grant 5R01HL117328-03) for supporting their studies of non-growing states.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Exponential phase
-
Microbial population growth that can fit to the exponential equation N(t)=N0 ekt, where N(t) is the population size at time t, N0 is the starting population size, e is the base of the natural logarithm, and k is a constant. Exponential growth is generally assumed to occur when no resource is limiting, to be balanced and at steady state.
- Stationary phase
-
A growth phase of microbial populations that occurs after at least one resource becomes limiting for growth. At the transition to stationary phase, the population continues to increase in size, but the rate of increase decreases; in stationary phase, the population size stops increasing.
- Adenylate energy charge
-
(AEC). A value based on the ratio of high energy phosphate bonds in ATP and ADP molecules to the total amount of adenylate in the cell.
- Antibiotic tolerance
-
The survival of cells that are exposed to high doses of antibiotics for periods of time that would usually be lethal. Antibiotic tolerance extends the length of time that a cell survives exposure to the drug, whereas resistance enables a cell to survive an increased concentration of the drug.
- Persisters
-
A subpopulation of cells that exhibits antibiotic tolerance in a population in which other cells are killed by the same dose and length of exposure to a drug. Persisters were first noted in an exponential-phase culture that was treated with high doses of antibiotics for extended periods of time.
- Anabolic
-
Metabolic reactions that construct larger macromolecules from smaller substrates.
- Catabolic
-
Metabolic reactions that break down macromolecules into smaller components for the generation of energy or for recycling.
- Reductive divisions
-
Cell divisions that are uncoupled from biosynthesis and growth, leading to progeny that are smaller in size. These contribute to the decrease in cell size that is observed during stationary phase.
- Glyoxylate shunt
-
An alternative to the standard tricarboxylic acid (TCA) cycle in which steps that generate reduced NAD(P)H are bypassed to enable succinate, fumarate, malate and oxaloacetate to be produced for biosynthetic reactions without generating reducing equivalents. The glyoxylate shunt is useful in the context of limitation for terminal electron acceptors or the catabolism of lipids.
- Anaplerotic
-
Reactions that replenish key intermediates of central metabolic cycles to compensate for their use by other biosynthetic pathways.
- Nucleoid
-
The chromosome and associated proteins.
- Sigma factor
-
A protein that recruits RNA polymerase to a specific set of promoters on DNA. Some sigma factors have large regulons, whereas others drive expression from only a few loci.
- Electrogenic secretion
-
Symport of a substrate (with its chemical gradient) and a proton (against its chemical gradient) that results in a net increase in the proton motive force across a membrane.
- Syntrophy
-
A mutually beneficial metabolic interaction between two (or more) species of microorganism.
- Stringent response
-
A conserved regulatory mechanism that coordinates the responses of bacteria to nutrient downshift. The response is mediated by the small-molecule alarmone (p)ppGpp, the synthesis of which from ATP and GDP or GTP is stimulated by uncharged tRNAs or disrupted lipid biosynthesis.
- Regulon
-
The group of genes that is regulated by a specific regulatory factor.
- Open promoter complexes
-
The intermediate in transcription initiation in which RNA polymerase has bound to a promoter and unwound the double-stranded DNA, which allows the template strand of the DNA to pass through the active site of the polymerase.
- Backtracked RNA polymerases
-
Transcribing RNA polymerases that slip backwards along a template after pausing, which causes the RNA–DNA hybrid at the 3′ end of the nascent transcript to unwind.
- Origin of replication
-
The site on the bacterial chromosome, determined by its sequence, where the two strands of DNA are unwound to enable replication of the chromosome to begin.
- Fenton reaction
-
A metal-catalysed free radical chain reaction in which Fe2+ is oxidized by H2O2 to produce OH− and OH•, which is a highly reactive radical species.
Rights and permissions
About this article
Cite this article
Bergkessel, M., Basta, D. & Newman, D. The physiology of growth arrest: uniting molecular and environmental microbiology. Nat Rev Microbiol 14, 549–562 (2016). https://doi.org/10.1038/nrmicro.2016.107
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrmicro.2016.107
This article is cited by
-
The fitness trade-off between growth and stress resistance determines the phenotypic landscape
BMC Biology (2024)
-
Synthetic microbiology in sustainability applications
Nature Reviews Microbiology (2024)
-
Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication
Nature Communications (2024)
-
Phototroph-heterotroph interactions during growth and long-term starvation across Prochlorococcus and Alteromonas diversity
The ISME Journal (2023)
-
Metabolomic profiling of bacterial biofilm: trends, challenges, and an emerging antibiofilm target
World Journal of Microbiology and Biotechnology (2023)