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  • Review Article
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The physiology of growth arrest: uniting molecular and environmental microbiology

Nature Reviews Microbiology volume 14, pages 549–562 (2016)Cite this article

Subjects

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.

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Figure 1: Metabolic rewiring during growth arrest.
Figure 2: Transcription and translation during different growth phases.
Figure 3: Overview of cellular morphology with emphasis on nucleoid.

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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.

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  1. California Institute of Technology (Caltech), 1200 East California Boulevard, Pasadena, 91125, California, USA

    Megan Bergkessel, David W. Basta & Dianne K. Newman

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  1. Megan Bergkessel
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Correspondence to Dianne K. Newman.

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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.

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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

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