Cited by 187Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyMycobacterium research and diagnosis

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Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity

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Rego, E. Hesper, Audette, Rebecca E., Rubin, Eric J.·2017·Nature

DOI 10.1038/nature22361PMC PMC5567998

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Abstract

Microorganisms are often studied as populations but the behaviour of single, individual cells can have important consequences. For example, tuberculosis, caused by the bacterial pathogen Mycobacterium tuberculosis, requires months of antibiotic therapy even though the bulk of the bacterial population dies rapidly. Shorter courses lead to high rates of relapse because subpopulations of bacilli can survive despite being genetically identical to those that are easily killed. In fact, mycobacteria create variability each time a cell divides, producing daughter cells with different sizes and growth rates. The mechanism(s) that underlie this high-frequency variation and how variability relates to survival of the population are unknown. Here we show that mycobacteria actively create heterogeneity. Using a fluorescent reporter and a fluorescence-activated cell sorting (FACS)-based transposon screen, we find that deletion of lamA, a gene of previously unknown function, decreases heterogeneity in the population by decreasing asymmetric polar growth. LamA has no known homologues in other organisms, but is highly conserved across mycobacterial species. We find that LamA is a member of the mycobacterial division complex (the 'divisome'). It inhibits growth at nascent new poles, creating asymmetry in polar growth. The kinetics of killing individual cells that lack lamA are more uniform and more rapid with rifampicin and drugs that target the cell wall. Our results show that mycobacteria encode a non-conserved protein that controls the pattern of cell growth, resulting in a population that is both heterogeneous and better able to survive antibiotic pressure.

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Authors: Rego, E. H., Audette, R. E., & Rubin, E. J.
Affiliations: Harvard University (US)
Corresponding author: Rego, E. Hesper
Rubin, Eric J.
ORCID: Rego, E. Hesper
Rubin, Eric J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-05-31
Volume: 546
Issue: 7656
Pages: 153-157
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature22361
PMC: PMC5567998
OpenAlex: W2617852583
Cited by: 186
References: 22
Citations by year: 2026: 14 · 2025: 15 · 2024: 18 · 2023: 16 · 2022: 23 · 2021: 16 · 2020: 25 · 2019: 22 · 2018: 30 · 2017: 7
FWCI: 17.68
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute of Allergy and Infectious Diseases (U19AI107774, F32AI104287)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
Keywords: lamas, divisome, Mycobacterium tuberculosis, cell wall synthesis inhibition, cell division, phenotypic heterogeneity, antibiotic tolerance, rifampicin, tuberculosis drug targets, single-cell heterogeneity
MeSH terms: Anti-Bacterial Agents, Bacterial Proteins, Cell Division, Cell Wall, DNA Mutational Analysis, Flow Cytometry, Fluoresceins, Phenotype, Rifampin, Reproducibility of Results, Cell Polarity, Gene Deletion, Mycobacterium smegmatis, Microbial Viability, Single-Cell Analysis

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Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity

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