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  • Review Article
  • Published:

How sisters grow apart: mycobacterial growth and division

Nature Reviews Microbiology volume 12, pages 550–562 (2014)Cite this article

Subjects

Key Points

  • The cell wall of mycobacteria is composed of complex macromolecules, and its composition differs from many other bacterial species, owing to the presence of mycolic acid and arabinogalactan layers. Cell wall synthesis is highly plastic, which leads to the generation of single cells that have distinct surfaces.

  • Mycobacterial growth is distinct from that of other rod-shaped bacteria. Rather than elongating by inserting peptidoglycan into the lateral cell wall, mycobacteria grow from their poles and divide asymmetrically. Two models that describe the processes of polar growth and asymmetric cell division are discussed.

  • The macromolecular machineries that are involved in cell growth and division in mycobacteria are organized differently from those in other model organisms. Many of the enzymes that form these complexes are required for the normal growth of mycobacteria, especially during infection.

  • Mycobacteria regulate cell proliferation via atypical mechanisms, including protein processing, phosphorylation of unique targets and pupylation (which is analogous to eukaryotic ubiquitylation).

  • The mycobacterial cell cycle produces population heterogeneity, owing to asymmetric cell division and stochastic epigenetic changes. This variability could facilitate the survival of M. tuberculosis in disparate physiological niches in the human host and promote antibiotic tolerance.

  • Substantial cell wall remodelling, particularly of the peptidoglycan and mycolic acid layers, occurs during infection. These changes increase the inherent population heterogeneity and may also promote survival in the human host.

Abstract

Mycobacterium tuberculosis, which is the aetiological agent of tuberculosis, owes much of its success as a pathogen to its unique cell wall and unusual mechanism of growth, which facilitate its adaptation to the human host and could have a role in clinical latency. Asymmetric growth and division increase population heterogeneity, which may promote antibiotic tolerance and the fitness of single cells. In this Review, we describe the unusual mechanisms of mycobacterial growth, cell wall biogenesis and division, and discuss how these processes might affect the survival of M. tuberculosis in vivo and contribute to the persistence of infection.

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Figure 1: Elongation and division of mycobacteria generates asymmetric daughter cells.
Figure 2: Protein machineries direct cell growth and division.
Figure 3: Regulatory mechanisms that control synthesis of the mycobacterial cell wall.
Figure 4: Cell wall remodelling may promote survival during infection.

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Acknowledgements

The authors thank S. Dove, C. Sassetti and S. Fortune for discussion of the ideas presented in this Review and C. Boutte, M. Chao and N. Peters for critical reading of the manuscript. The authors thank J. McKinney and anonymous referees for excellent suggestions and improvements and A. Goranov for discussion of cell growth models. Support was provided by the US National Institutes of Health (NIH) (grant number U01-GM094568 to E.J.R.) and the US National Science Foundation (NSF) Graduate Research Fellowship (grant number DGE-1144152 to K.J.K.).

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Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Karen J. Kieser & Eric J. Rubin

  2. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Eric J. Rubin

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  1. Karen J. Kieser
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Correspondence to Eric J. Rubin.

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Main cell elongation and division proteins (PDF 201 kb)

Glossary

Granuloma

An organized cellular structure that forms owing to the immune response to an invading pathogen. An array of immune and fibrotic cells 'wall-off' the invading pathogen in an attempt to limit its spread within the host.

Latency

An asymptomatic disease state in which the bacterial burden is low or undetectable.

Non-traditional 3–3 peptide crosslinks

Peptide bonds between the third residues (meso-diaminopimelic acid (mDAP) in mycobacteria) of two peptide tails in peptidoglycan; a traditional crosslink is a peptide bond between the third and fourth residues (between DAP and D-Ala in mycobacteria) of two peptide tails.

Cytokinesis

The process in which a plasma membrane forms in the mid-cell region of a mother cell during cell division.

Septum

A layer of peptidoglycan that is formed at approximately mid-cell (in mycobacteria) that generates a physical barrier between nascent daughter cells.

Microfluidics

A technology in which small fabricated chambers are used to isolate and image single cells.

Microcolonies

Groups of progeny cells that are generated from the growth and division of single cells.

Periplasm

The extracellular space between the plasma membrane and the outer membrane of Gram-negative bacteria. The mycolic acid layer of mycobacteria functions analogously to an outer membrane, and thus, the space between the plasma membrane and the mycolic acid layer is known as the periplasm in mycobacteria.

Actinobacteria

A phylum of bacteria to which mycobacteria belong. This phylum also includes species such as Streptomyces coelicolor and Corynebacterium glutamicum.

Phosphomimetic

An amino acid substitution, typically by an aspartic acid or glutamic acid, at the site of a phosphorylated residue in a protein, which mimics constitutive phosphorylation.

MinCDE system

A protein system in Escherichia coli that regulates placement of the division septum in the cell. MinCDE oscillate from pole-to-pole and establish a concentration gradient to prevent Z-ring formation at the cell poles.

SOS response

A response to DNA damage in which bacteria halt cell cycle progression and induce DNA repair mechanisms in an effort to repair the chromosome before continuing division.

FASI and FASII complexes

(Fatty acid synthase I and II complexes). Complexes that are involved in mycolic acid synthesis. FASI, which is composed of the protein Fas, synthesizes the initial C20–C26 α-branch of mycolic acids. This branch is joined to a C60–C90 meromycolate branch that is synthesized by the FASII complex, which is composed of MabA, HadABC, InhA, KasAB and an unidentified isomerase.

Pupylation

A system that typically targets proteins for proteasomal degradation by the addition of a small prokaryotic ubiquitin-like protein (Pup). Pupylation directs some, but not all, of its targets to the proteasome, which suggests that pupylation may have additional roles in regulating protein activity.

Chemostat

A closed system for bacterial growth that is used to control the bacterial replication rate and/or metabolism by the use of chemically defined media.

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Kieser, K., Rubin, E. How sisters grow apart: mycobacterial growth and division. Nat Rev Microbiol 12, 550–562 (2014). https://doi.org/10.1038/nrmicro3299

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