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Cited by 281Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyInfectious Diseases and Tuberculosis

The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin

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Gupta, Radhika, Lavollay, Marie, Mainardi, Jean-Luc, Arthur, Michel, Bishai, William R, Lamichhane, Gyanu·2010·Nature Medicine
DOI 10.1038/nm.2120PMC PMC2851841
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Abstract

The peptidoglycan layer is a vital component of the bacterial cell wall. The existing paradigm describes the peptidoglycan network as a static structure that is cross-linked predominantly by 4-->3 transpeptide linkages. However, the nonclassical 3-->3 linkages predominate the transpeptide networking of the peptidoglycan layer of nonreplicating Mycobacterium tuberculosis. The molecular basis of these linkages and their role in the physiology of the peptidoglycan layer, virulence and susceptibility of M. tuberculosis to drugs remain undefined. Here we identify MT2594 as an L,D-transpeptidase that generates 3-->3 linkages in M. tuberculosis. We show that the loss of this protein leads to altered colony morphology, loss of virulence and increased susceptibility to amoxicillin-clavulanate during the chronic phase of infection. This suggests that 3-->3 cross-linking is vital to the physiology of the peptidoglycan layer. Although a functional homolog exists, expression of ldtMt2 is dominant throughout the growth phases of M. tuberculosis. 4-->3 transpeptide linkages are targeted by one of the most widely used classes of antibacterial drugs in human clinical use today, beta-lactams. Recently, meropenem-clavulanate was shown to be effective against drug-resistant M. tuberculosis. Our study suggests that a combination of L,D-transpeptidase and beta-lactamase inhibitors could effectively target persisting bacilli during the chronic phase of tuberculosis.

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  • LdtA may be upregulated in stasis, and LdtB is required for chronic phase survival.

    “Ldta may be upregulated in stasis59, and LdtB is required for chronic phase survival147.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [147]

    Citation 147 attaches to the LdtB chronic-survival claim, not the LdtA expression claim. In the paper’s infection-results passage (section labeled Abstract; page unavailable), mice infected with the ldtMt2 mutant still had approximately 10,000 bacteria in their lungs during the persistent stage. The paper reports attenuated persistence, not that this gene is required for survival in that stage. (LLM, conf=0.86)

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Research works printed but not linked: 27

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Cited by

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Authors
Gupta, R., Lavollay, M., Mainardi, J.-L., Arthur, M., Bishai, W. R., & Lamichhane, G.
Affiliations
  • Johns Hopkins University (US)
  • Inserm (FR)
Corresponding author
Lamichhane, Gyanu
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2010-03-21
Volume
16
Issue
4
Pages
466-469
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2120
PMC
PMC2851841
OpenAlex
W2070190311
Cited by
281
References
1
Citations by year
2026: 10 · 2025: 13 · 2024: 14 · 2023: 10 · 2022: 14 · 2021: 24 · 2020: 14 · 2019: 32 · 2018: 24 · 2017: 24 · 2016: 17 · 2015: 18 · 2014: 14 · 2013: 18 · 2012: 16
FWCI
10.99
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (n01ai30036-6-0-0)
  • National Institute of Allergy and Infectious Diseases (AI 30036, N01 AI030036)
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 › Surgery › Infectious Diseases and Tuberculosis
Keywords
Mycobacterium tuberculosis, L,D-transpeptidase, peptidoglycan, virulence, amoxicillin resistance, amoxicillin-clavulanic acid, beta-lactam resistance, beta-lactamase inhibitors, chronic tuberculosis, cell wall
MeSH terms
Amoxicillin, Animals, Antitubercular Agents, Humans, Mice, Inbred BALB C, Microbial Sensitivity Tests, Models, Biological, Mycobacterium tuberculosis, Penicillin Resistance, Peptidoglycan, Tuberculosis, Pulmonary, Aminoacyltransferases, Mice

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