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Cited by 466Mycobacterium research and diagnosisTuberculosis Research and EpidemiologyBacterial Genetics and Biotechnology

The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.

The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for the antimycobacterial drug ethambutol.

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Belanger, A E, Besra, G S, Ford, M E, Mikusová, K, Belisle, J T, Brennan, P J, Inamine, J M·1996·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.93.21.11919PMC PMC38159
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Abstract

The antimycobacterial compound ethambutol [Emb; dextro-2,2'-(ethylenediimino)-di-1-butanol] is used to treat tuberculosis as well as disseminated infections caused by Mycobacterium avium. The critical target for Emb lies in the pathway for the biosynthesis of cell wall arabinogalactan, but the molecular mechanisms for drug action and resistance are unknown. The cellular target for Emb was sought using drug resistance, via target overexpression by a plasmid vector, as a selection tool. This strategy led to the cloning of the M. avium emb region which rendered the otherwise susceptible Mycobacterium smegmatis host resistant to Emb. This region contains three complete open reading frames (ORFs), embR, embA, and embB. The translationally coupled embA and embB genes are necessary and sufficient for an Emb-resistant phenotype which depends on gene copy number, and their putative novel membrane proteins are homologous to each other. The predicted protein encoded by embR, which is related to known transcriptional activators from Streptomyces, is expendable for the phenotypic expression of Emb resistance, but an intact divergent promoter region between embR and embAB is required. An Emb-sensitive cell-free assay for arabinan biosynthesis shows that overexpression of embAB is associated with high-level Emb-resistant arabinosyl transferase activity, and that embR appears to modulate the in vitro level of this activity. These data suggest that embAB encode the drug target of Emb, the arabinosyl transferase responsible for the polymerization of arabinose into the arabinan of arabinogalactan, and that overproduction of this Emb-sensitive target leads to Emb resistance.

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  • A plasmid library of M. avium chromosomal fragments was screened for clones exhibiting resistance to EMB, identifying 2 arabinosyltransferases, EmbA and B, as mediating resistance to EMB.

    “A plasmid library of M. avium chromosomal fragments were screened for clones exhibiting resistance to EMB. This screen identified 2 arabinosyltransferases, EmbA and B, as mediating resistance to EMB (141).”

    From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [141]

    The Results (p. 3) describe screening an M. avium genomic library for clones that conferred ethambutol resistance in M. smegmatis. The paper reports that embA and embB are necessary and sufficient for the resistant phenotype, but the Discussion (p. 5) links the genes jointly to arabinosyltransferase activity; it does not establish EmbA and EmbB as two separate arabinosyltransferases. (LLM, conf=0.84)

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  • Loss of glycosylation in plants, fungi or prokaryotes can also lead to cell death.

    “While space does not allow a detailed discussion, loss of glycosylation in plants, fungi or prokaryotes can also lead to cell death.”

    From Biological roles of glycans (2017) · cites this paper as [434]

    The Results (p. 4) show that ethambutol reduces incorporation of arabinose into a mycobacterial cell-wall component, and Materials and Methods (p. 2) describe its inhibition of bacterial growth. The paper does not show that this loss causes cell death, or address plants or fungi. (LLM, conf=0.82)

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Research works printed but not linked: 2

  1. [6]Draper, P. (1982) in The Biology of the Mycobacteria, eds. Ratiedge, C. & Stanford, J. (Academic, London), Vol. 1, pp. 9-52.
  2. [19]Lee, M. H., Pascopella, L., Jacobs, W. R., Jr., & Hatfull, G. F. (1991) Proc. Natl. Acad. Sci. USA 88, 3111–3115.

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Metadata

Authors
Belanger, A. E., Besra, G. S., Ford, M. E., Mikusová, K., Belisle, J. T., Brennan, P. J., & Inamine, J. M.
Affiliations
  • Colorado State University (US)
  • University of Pittsburgh (US)
  • Department of Microbiology, Colorado State University, Fort Collins 80523, USA.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1996-10-15
Volume
93
Issue
21
Pages
11919-11924
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.93.21.11919
PMC
PMC38159
OpenAlex
W2011128355
Cited by
466
References
34
Citations by year
2026: 15 · 2025: 7 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 11 · 2020: 19 · 2019: 16 · 2018: 13 · 2017: 17 · 2016: 25 · 2015: 28 · 2014: 26 · 2013: 12 · 2012: 28
FWCI
12.27
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5u01ai030189-03, 5u19ai038087-04)
  • National Institute of Allergy and Infectious Diseases (AI38087, AI 33706, R01AI033706, AI30189)
Topics
  • Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
ethambutol, Mycobacterium avium, arabinogalactan, antimycobacterial drug resistance, drug target identification, gene copy number, Mycobacterium smegmatis
MeSH terms
Amino Acid Sequence, Antitubercular Agents, Base Sequence, Cell Wall, Cloning, Molecular, Drug Resistance, Microbial, Ethambutol, Galactans, Genes, Bacterial, Microbial Sensitivity Tests, Molecular Sequence Data, Mycobacterium avium, Pentosyltransferases, Recombinant Proteins, Restriction Mapping, Open Reading Frames, Sequence Homology, Amino Acid

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