The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol

Amalio Telenti, Wolfgang J. Philipp, Srinand Sreevatsan, Claudia Bernasconi, Kathryn E. Stockbauer, Brigitte Wieles, James M. Musser, William R. Jacobs

Research output: Contribution to journalArticle

319 Citations (Scopus)

Abstract

Ethambutol (EMB), a frontline antituberculous drug, targets the mycobacterial cell wall, a unique structure among prokaryotes which consists of an outer layer of mycolic acids covalently bound to peptidoglycan via the arabinogalactan. EMB inhibits the polymerization of cell wall arabinan, and results in the accumulation of the lipid carrier decaprenol phosphoarabinose, which suggests that the drug interferes with the transfer of arabinose to the cell wall acceptor. Unfortunately, resistance to EMB has been described in up to 4% of clinical isolates of Mycobacterium tuberculosis and is prevalent among isolates from patients with multidrug-resistant tuberculosis. We used resistance to EMB as a tool to identify genes participating in the biosynthesis of the mycobacterial cell wall. This approach led to the identification of the embCAB gene cluster, recently proposed to encode for mycobacterial arabinosyl transferases. Resistance to EMB results from an accumulation of genetic events determining overexpression of the Emb protein(s), structural mutation in EmbB, or both. Further characterization of these proteins might provide information on targets for new chemotherapeutic agents and might help development of diagnostic strategies for the detection of resistant M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)567-570
Number of pages4
JournalNature Medicine
Volume3
Issue number5
DOIs
StatePublished - Jan 1 1997

Fingerprint

Ethambutol
Operon
Multigene Family
Mycobacterium tuberculosis
Genes
Cell Wall
Cells
Mycolic Acids
Multidrug-Resistant Tuberculosis
Arabinose
Peptidoglycan
Biosynthesis
Polymerization
Pharmaceutical Preparations
Proteins
Lipids
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Telenti, A., Philipp, W. J., Sreevatsan, S., Bernasconi, C., Stockbauer, K. E., Wieles, B., ... Jacobs, W. R. (1997). The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nature Medicine, 3(5), 567-570. https://doi.org/10.1038/nm0597-567

The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. / Telenti, Amalio; Philipp, Wolfgang J.; Sreevatsan, Srinand; Bernasconi, Claudia; Stockbauer, Kathryn E.; Wieles, Brigitte; Musser, James M.; Jacobs, William R.

In: Nature Medicine, Vol. 3, No. 5, 01.01.1997, p. 567-570.

Research output: Contribution to journalArticle

Telenti, A, Philipp, WJ, Sreevatsan, S, Bernasconi, C, Stockbauer, KE, Wieles, B, Musser, JM & Jacobs, WR 1997, 'The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol', Nature Medicine, vol. 3, no. 5, pp. 567-570. https://doi.org/10.1038/nm0597-567
Telenti A, Philipp WJ, Sreevatsan S, Bernasconi C, Stockbauer KE, Wieles B et al. The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nature Medicine. 1997 Jan 1;3(5):567-570. https://doi.org/10.1038/nm0597-567
Telenti, Amalio ; Philipp, Wolfgang J. ; Sreevatsan, Srinand ; Bernasconi, Claudia ; Stockbauer, Kathryn E. ; Wieles, Brigitte ; Musser, James M. ; Jacobs, William R. / The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. In: Nature Medicine. 1997 ; Vol. 3, No. 5. pp. 567-570.
@article{4302eabfe80b4dcd937bf60f93394134,
title = "The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol",
abstract = "Ethambutol (EMB), a frontline antituberculous drug, targets the mycobacterial cell wall, a unique structure among prokaryotes which consists of an outer layer of mycolic acids covalently bound to peptidoglycan via the arabinogalactan. EMB inhibits the polymerization of cell wall arabinan, and results in the accumulation of the lipid carrier decaprenol phosphoarabinose, which suggests that the drug interferes with the transfer of arabinose to the cell wall acceptor. Unfortunately, resistance to EMB has been described in up to 4{\%} of clinical isolates of Mycobacterium tuberculosis and is prevalent among isolates from patients with multidrug-resistant tuberculosis. We used resistance to EMB as a tool to identify genes participating in the biosynthesis of the mycobacterial cell wall. This approach led to the identification of the embCAB gene cluster, recently proposed to encode for mycobacterial arabinosyl transferases. Resistance to EMB results from an accumulation of genetic events determining overexpression of the Emb protein(s), structural mutation in EmbB, or both. Further characterization of these proteins might provide information on targets for new chemotherapeutic agents and might help development of diagnostic strategies for the detection of resistant M. tuberculosis.",
author = "Amalio Telenti and Philipp, {Wolfgang J.} and Srinand Sreevatsan and Claudia Bernasconi and Stockbauer, {Kathryn E.} and Brigitte Wieles and Musser, {James M.} and Jacobs, {William R.}",
year = "1997",
month = "1",
day = "1",
doi = "10.1038/nm0597-567",
language = "English (US)",
volume = "3",
pages = "567--570",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol

AU - Telenti, Amalio

AU - Philipp, Wolfgang J.

AU - Sreevatsan, Srinand

AU - Bernasconi, Claudia

AU - Stockbauer, Kathryn E.

AU - Wieles, Brigitte

AU - Musser, James M.

AU - Jacobs, William R.

PY - 1997/1/1

Y1 - 1997/1/1

N2 - Ethambutol (EMB), a frontline antituberculous drug, targets the mycobacterial cell wall, a unique structure among prokaryotes which consists of an outer layer of mycolic acids covalently bound to peptidoglycan via the arabinogalactan. EMB inhibits the polymerization of cell wall arabinan, and results in the accumulation of the lipid carrier decaprenol phosphoarabinose, which suggests that the drug interferes with the transfer of arabinose to the cell wall acceptor. Unfortunately, resistance to EMB has been described in up to 4% of clinical isolates of Mycobacterium tuberculosis and is prevalent among isolates from patients with multidrug-resistant tuberculosis. We used resistance to EMB as a tool to identify genes participating in the biosynthesis of the mycobacterial cell wall. This approach led to the identification of the embCAB gene cluster, recently proposed to encode for mycobacterial arabinosyl transferases. Resistance to EMB results from an accumulation of genetic events determining overexpression of the Emb protein(s), structural mutation in EmbB, or both. Further characterization of these proteins might provide information on targets for new chemotherapeutic agents and might help development of diagnostic strategies for the detection of resistant M. tuberculosis.

AB - Ethambutol (EMB), a frontline antituberculous drug, targets the mycobacterial cell wall, a unique structure among prokaryotes which consists of an outer layer of mycolic acids covalently bound to peptidoglycan via the arabinogalactan. EMB inhibits the polymerization of cell wall arabinan, and results in the accumulation of the lipid carrier decaprenol phosphoarabinose, which suggests that the drug interferes with the transfer of arabinose to the cell wall acceptor. Unfortunately, resistance to EMB has been described in up to 4% of clinical isolates of Mycobacterium tuberculosis and is prevalent among isolates from patients with multidrug-resistant tuberculosis. We used resistance to EMB as a tool to identify genes participating in the biosynthesis of the mycobacterial cell wall. This approach led to the identification of the embCAB gene cluster, recently proposed to encode for mycobacterial arabinosyl transferases. Resistance to EMB results from an accumulation of genetic events determining overexpression of the Emb protein(s), structural mutation in EmbB, or both. Further characterization of these proteins might provide information on targets for new chemotherapeutic agents and might help development of diagnostic strategies for the detection of resistant M. tuberculosis.

UR - http://www.scopus.com/inward/record.url?scp=0030913996&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030913996&partnerID=8YFLogxK

U2 - 10.1038/nm0597-567

DO - 10.1038/nm0597-567

M3 - Article

C2 - 9142129

AN - SCOPUS:0030913996

VL - 3

SP - 567

EP - 570

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 5

ER -