Maturing Mycobacterium smegmatis peptidoglycan requires non-canonical crosslinks to maintain shape
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In most well-studied rod-shaped bacteria, peptidoglycan is primarily crosslinked by penicillin-binding proteins (PBPs). However, in mycobacteria, crosslinks formed by L,D-transpeptidases (LDTs) are highly abundant. To elucidate the role of these unusual crosslinks, we characterized Mycobacterium smegmatis cells lacking all LDTs. We find that crosslinks generate by LDTs are required for rod shape maintenance specifically at sites of aging cell wall, a byproduct of polar elongation. Asymmetric polar growth leads to a non-uniform distribution of these two types of crosslinks in a single cell. Consequently, in the absence of LDT-mediated crosslinks, PBP-catalyzed crosslinks become more important. Because of this, Mycobacterium tuberculosis (Mtb) is more rapidly killed using a combination of drugs capable of PBP- and LDT- inhibition. Thus, knowledge about the spatial and genetic relationship between drug targets can be exploited to more effectively treat this pathogen.
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Peptidoglycan chemistry likely varies across the length of the cell, with d-d crosslinks at the poles and septum and more l-d crosslinks at the middle of the cell.
“Thus, peptidoglycan chemistry likely varies across the length of the cell, with d–d crosslinks at the poles and septum and more l–d crosslinks at the middle of the cell36 (Fig. 1a).”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [36]
The Results section on enzyme localization and the Discussion support the proposed gradient: 4–3 (d–d) crosslinks are associated with newer peptidoglycan near the poles, while 3–3 (l–d) crosslinks are associated with older material toward mid-cell. The paper does not establish d–d crosslinks at the septum; its Discussion instead notes a local minimum of the relevant enzyme-localization patterns near the division site. (LLM, conf=0.86)
Experimental — accuracy not yet measuredL,D-transpeptidases catalyse peptidoglycan remodelling.
“l,d-transpeptidases catalyse peptidoglycan remodelling36.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [36]
In Mycobacterium smegmatis, peptidoglycan construction for growth occurs mostly through penicillin-binding proteins, which therefore may be poor drug targets during stasis.
“in Mycobacterium smegmatis, peptidoglycan construction for growth occurs mostly through penicillin-binding proteins36, which therefore may be poor drug targets during stasis.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [36]
The chemical structure of peptidoglycan varies across the length of the cell.
“This article makes a strong argument, through meticulous though necessarily indirect experiments, that the chemical structure of peptidoglycan varies across the length of the cell.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [36]
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Asymmetry and Aging of Mycobacterial Cells Lead to Variable Growth and Antibiotic Susceptibility
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Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity
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- Authors
- Baranowski, C., Welsh, M. A., Sham, L.-T., Eskandarian, H. A., Lim, H. C., Kieser, K. J., Wagner, J. C., McKinney, J. D., Fantner, G. E., Ioerger, T. R., Walker, S., Bernhardt, T. G., Rubin, E. J., & Rego, E. H.
- Affiliations
- Harvard University (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Texas A&M University (US)
- Yale University (US)
- Corresponding author
- Rubin, Eric J
- Rego, E Hesper
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-10-16
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6231781
- OpenAlex
- W2897723297
- Cited by
- 132
- References
- 3
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 12 · 2023: 15 · 2022: 21 · 2021: 23 · 2020: 20 · 2019: 16 · 2018: 4
- FWCI
- 11.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (U19 AI107774, F32AI104287, R01 GM76710, R01AI083365, F32GM123579, U19AI109764)
- Burroughs Wellcome Fund (Career Award at the Scientific Interface)
- American Heart Association (14POST18480014)
- Simons Foundation (Fellow of the Life Sciences Research Foundation Award)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_156945, 205321_134786, 205320_152675)
- Seventh Framework Programme (FP7/2007-2013/ERC Grant agreement No. 307338 (NaMic))
- European Molecular Biology Organization (191-2014, 750-2016)
- National Science Foundation (DGE1144152, DGE0946799)
- Innovative Medicines Initiative (115337)
- EU-FP7/Eurostars (E!8213)
- 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 › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Keywords
- Mycobacterium smegmatis, Mycobacterium tuberculosis, peptidoglycan cross-linking, L,D-transpeptidase, penicillin-binding proteins, bacterial cell shape, antibiotic synergy
- MeSH terms
- Meropenem, Amino Acids, Amoxicillin, Bacillus, Cell Wall, Cross-Linking Reagents, Escherichia coli, Fluorescence, Kinetics, Models, Biological, Peptidoglycan, Aminoacyltransferases, Mycobacterium smegmatis, Penicillin-Binding Proteins, Microbial Viability
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