Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity
Open accessAbstract
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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A mutant of M. smegmatis lacking lamA elongates and divides symmetrically.
“Strikingly, asymmetric division is an actively regulated process, not the result of random septal placement; a mutant of M. smegmatis lacking lamA elongates and divides symmetrically (124).”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [124]
The Main Text reports that ΔlamA M. smegmatis cells add cell wall material at much more similar rates at their old and new poles, supporting more symmetric elongation. It also reports reduced asymmetry in daughter-cell calcein accumulation at division, but does not establish fully symmetric division or show that septal placement is nonrandom. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLamA localizes to the septum, interacts with PBP PonA1 and inhibits growth at the developing new pole.
“LamA localizes to the septum, where it interacts with the PBP PonA1 and inhibits growth at the developing new pole.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [40]
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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.
- Venue
- Nature
- Published
- 2017-05-31
- Volume
- 546
- Issue
- 7656
- Pages
- 153-157
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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