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
- PMID: 8876238
- PMCID: PMC38159
- DOI: 10.1073/pnas.93.21.11919
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
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.
Similar articles
-
A single point mutation in the embB gene is responsible for resistance to ethambutol in Mycobacterium smegmatis.Antimicrob Agents Chemother. 1997 Dec;41(12):2629-33. doi: 10.1128/AAC.41.12.2629. Antimicrob Agents Chemother. 1997. PMID: 9420031 Free PMC article.
-
The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol.Nat Med. 1997 May;3(5):567-70. doi: 10.1038/nm0597-567. Nat Med. 1997. PMID: 9142129
-
Mutations in the embC-embA intergenic region contribute to Mycobacterium tuberculosis resistance to ethambutol.Antimicrob Agents Chemother. 2014 Nov;58(11):6837-43. doi: 10.1128/AAC.03285-14. Epub 2014 Sep 2. Antimicrob Agents Chemother. 2014. PMID: 25182646 Free PMC article.
-
Mycobacterial ethambutol responsive genes and implications in antibiotics resistance.J Drug Target. 2021 Mar;29(3):284-293. doi: 10.1080/1061186X.2020.1853733. Epub 2020 Dec 3. J Drug Target. 2021. PMID: 33210572 Review.
-
Diagnostic accuracy of a molecular drug susceptibility testing method for the antituberculosis drug ethambutol: a systematic review and meta-analysis.J Clin Microbiol. 2014 Aug;52(8):2913-24. doi: 10.1128/JCM.00560-14. Epub 2014 Jun 4. J Clin Microbiol. 2014. PMID: 24899018 Free PMC article. Review.
Cited by
-
Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant Mycobacterium tuberculosis.mBio. 2024 Mar 13;15(3):e0296823. doi: 10.1128/mbio.02968-23. Epub 2024 Jan 31. mBio. 2024. PMID: 38294237 Free PMC article.
-
Identification and Analysis of Candidate Genes Associated with Yield Structure Traits and Maize Yield Using Next-Generation Sequencing Technology.Genes (Basel). 2023 Dec 29;15(1):56. doi: 10.3390/genes15010056. Genes (Basel). 2023. PMID: 38254946 Free PMC article.
-
Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity.Naunyn Schmiedebergs Arch Pharmacol. 2024 Mar;397(3):1251-1273. doi: 10.1007/s00210-023-02679-z. Epub 2023 Sep 4. Naunyn Schmiedebergs Arch Pharmacol. 2024. PMID: 37665346 Review.
-
Structure of the priming arabinosyltransferase AftA required for AG biosynthesis of Mycobacterium tuberculosis.Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2302858120. doi: 10.1073/pnas.2302858120. Epub 2023 May 30. Proc Natl Acad Sci U S A. 2023. PMID: 37252995 Free PMC article.
-
Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line.Genet Mol Biol. 2023 Jan 23;46(1 Suppl 2):e20220261. doi: 10.1590/1678-4685-GMB-2022-0261. eCollection 2023. Genet Mol Biol. 2023. PMID: 36718771 Free PMC article.
References
Publication types
MeSH terms
Substances
Associated data
- Actions
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases