Abstract
Model bacteria, such as E. coli and B. subtilis, tightly regulate cell cycle progression to achieve consistent cell size distributions and replication dynamics. Many of the hallmark features of these model bacteria, including lateral cell wall elongation and symmetric growth and division, do not occur in mycobacteria. Instead, mycobacterial growth is characterized by asymmetric polar growth and division. This innate asymmetry creates unequal birth sizes and growth rates for daughter cells with each division, generating a phenotypically heterogeneous population. Although the asymmetric growth patterns of mycobacteria lead to a larger variation in birth size than typically seen in model bacterial populations, the cell size distribution is stable over time. Here, we review the cellular mechanisms of growth, division, and cell cycle progression in mycobacteria in the face of asymmetry and inherent heterogeneity. These processes coalesce to control cell size. Although Mycobacterium smegmatis and Mycobacterium bovis Bacillus Calmette-Guérin (BCG) utilize a novel model of cell size control, they are similar to previously studied bacteria in that initiation of DNA replication is a key checkpoint for cell division. We compare the regulation of DNA replication initiation and strategies used for cell size homeostasis in mycobacteria and model bacteria. Finally, we review the importance of cellular organization and chromosome segregation relating to the physiology of mycobacteria and consider how new frameworks could be applied across the wide spectrum of bacterial diversity.
Highlights
Mycobacteria are unusual compared to other well-studied bacteria
Much of the knowledge of basic cell cycle and growth processes developed in well-studied bacteria cannot be directly translated to mycobacteria
Molecular support for the hypothesis that phenotypic heterogeneity promotes bacterial survival comes from studies using the symmetrically growing LamA mutant. lamA M. smegmatis and M. tuberculosis show less size heterogeneity than wild type cells and are killed more rapidly and uniformly by rifampicin and cell wall acting antibiotics (Rego et al, 2017). This molecular study, together with population level studies, support the hypothesis that asymmetric polar growth actively creates heterogeneity amongst bacterial cells to serve as a bulk survival mechanism, ensuring a subpopulation of M. tuberculosis can persist in stressful environments
Summary
They grow slowly, are not stained by dyes traditionally used to identify and differentiate bacteria, and have remarkably thick and waxy cell walls (Jankute et al, 2015) They have a similar rod shaped morphology as many model bacterial species, recent attention to their basic physiology demonstrates distinct growth modes, subcellular organization, cell cycle timing, division patterns, and size control. Due to these differences, much of the knowledge of basic cell cycle and growth processes developed in well-studied bacteria cannot be directly translated to mycobacteria. These models, provide valuable context for studying how the basic physiology of mycobacteria fits into the spectrum of previously studied microorganisms
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