Signals of growth regulation in bacteria

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A fundamental characteristic of cells is their ability to regulate growth in response to changing environmental conditions. This review focuses on recent progress toward understanding the mechanisms by which bacterial growth is regulated. These phenomena include the ‘viable but not culturable’ (VBNC) state, in which bacterial growth becomes conditional, and ‘persistence’, which confers antibiotic resistance to a small fraction of bacteria in a population. Notably, at least one form of persistence appears to involve the generation of nongrowing phenotypic variants after transition through stationary phase. The possible roles of toxin–antitoxin modules in growth control are explored, as well as other mechanisms including contact-dependent growth inhibition, which regulates cellular metabolism and growth through binding to an outer membrane protein receptor.

Introduction

This review focuses on recent advances in our understanding of bacterial growth regulation, with an emphasis on the mechanisms that control entry and exit from a slow growth or nongrowth (dormant) state, excluding spore formation. This topic has relevance to a number of important aspects of bacterial biology including resistance of a small fraction of a bacterial population to killing by an antibiotic, termed ‘persistence’. The maintenance of bacterial viability without growth impacts human health in a number of ways including maintenance of pathogen reservoirs and chronic infections such as tuberculosis and melioidosis. This has been a difficult area of research, in part due to phenotypic variability in which only a small fraction of bacteria are within a dormant state in a population, making it hard to isolate and study dormant cells. Moreover, since many genes influence cell growth, it has been a challenge to identify those that constitute specific pathway(s) for dormancy/antibiotic resistance. Our aim in this review is to delineate some of the key findings and concepts in growth control, bringing together new developments in different fields of research that may impinge on one another.

Section snippets

The viable but not culturable (VBNC) state

Colwell and coworkers first reported that bacteria can fail to grow on laboratory media but still appear viable on the basis of outer membrane integrity and the ability to recover growth through temperature shifts [1]. This phenomenon, termed ‘viable but not culturable’ (VBNC), has now been described for over 50 bacterial species using various criteria for viability including propidium iodide exclusion, redox activity, and green fluorescent protein reporter expression, but of course none of

Contact-dependent growth inhibition

Recently a phenomenon called ‘contact-dependent growth inhibition’ or CDI was described, in which cell growth is controlled by direct cell-to-cell contact mediated by the CdiA–CdiB two-partner secretion (TPS) system. CdiA–CdiB is present in certain Escherichia coli strains, and homologous proteins are found in many bacterial species [6]. By homology with other TPS systems, CdiB appears to be an outer membrane protein required for the transport and assembly of CdiA at the cell surface. The CDI

Other growth control mechanisms

Other interesting phenomena involving control of cell growth and metabolism have been recently described. An evolved variant of E. coli K-12 was shown to inhibit its ancestral form in stationary phase, through a contact-mediated process called stationary contact-dependent growth inhibition or SCDI [10]. In eight independent cultures the glgC gene involved in glycogen metabolism was affected, with resulting overexpression of glycogen. In parallel with CDI, there is an immunity component to SCDI

Chromosomal TA modules as modulators of growth

Toxin–antitoxin modules (hereafter termed TA modules) are widely distributed, two-component systems implicated in bacterial growth control [17]. TA modules encode a stable ‘toxin’ protein, whose activity results in either growth arrest or cell death, and an unstable ‘antitoxin’ that counteracts toxin activity (Figure 2A). Antitoxins are either antisense RNAs that suppress toxin expression, or labile proteins that bind and inactivate their cognate toxin (for a comprehensive review of TA modules,

Persistence, a mechanism for growth control by phenotypic variation

A phenomenon called ‘persistence’ was previously described in which addition of penicillin to cultures of Staphylococci killed most of the cells, but rare ‘persister’ cells survived. Persistence is not a genetically heritable trait, and thus differs from the many mechanisms known by which bacteria can become resistant to antibiotics [37, 38]. The low frequency and nonheritable characteristics of persister cells have made it difficult to isolate pure populations for study, and thus progress in

Conclusions

Identification of the signaling mechanisms that regulate cellular growth is critical to understand how microbes colonize diverse environments. Bacterial generation times are generally short, allowing them to play a bet-hedging strategy in which phenotypic variation is generated by mutation. Many of these mechanisms are well understood due in large part to the ease with which mutants can be isolated. In addition, a number of epigenetic phenomena have been identified, including the VBNC and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank S Aoki and B Braaten for reviewing the manuscript. We are grateful to the National Science Foundation (NSF grant 0642052 (DAL)) and to the National Institutes of Health [grant GM078634 (CSH) and grant 1U54 AI065359 of the Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious Disease (DAL)] for support of research in our laboratories.

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