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.

Belanger, Aimee E.; Besra, Gurdyal S.; Ford, Michael E.; Mikušová, Katarı́na; Belisle, John T.; Brennan, Patrick J.; Inamine, Julia M.

doi:10.1073/pnas.93.21.11919

Cited by 404 publications

(323 citation statements)

References 30 publications

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“…[2]. For EMB, this finding is more surprising because the drug inhibits the polymerization of arabinose found in arabinogalactan and LAM [4]. Because we showed that the drug removes mycolic acids, our data suggest that LAM and arabinogalactan -onto which mycolic acids are attached -are not repressed in the same way, which is actually consistent with previous studies [11,13,21,22,27].…”

Section: Structural Changes Correlate With Differences In Chemical Prsupporting

confidence: 91%

“…Ethionamide (ETH) and isoniazid (INH) inhibit the enoyl ACP reductase InhA involved in the biosynthesis of mycolic acids [2], while the synthesis of the glycosylated portion of the wall is efficiently inhibited by ethambutol (EMB), which targets arabinosyltransferases [4]. Streptomycin (STR) targets the 30S subunit of ribosomes, leading to an inhibition of protein synthesis [30].…”

Section: Introductionmentioning

confidence: 99%

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Organization of the mycobacterial cell wall: a nanoscale view

Alsteens

Verbelen

Dague

et al. 2007

Pflugers Arch - Eur J Physiol

109

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The biosynthesis of the Mycobacterium tuberculosis cell wall is targeted by some of the most powerful antituberculous drugs. To date, the molecular mechanisms by which these antibiotics affect the cell wall characteristics are not well understood. Here, we used atomic force microscopy -in three different modes -to probe the nanoscale surface properties of live mycobacteria and their modifications upon incubation with four antimycobacterial drugs: isoniazid, ethionamide, ethambutol, and streptomycine. Topographic imaging, combined with quantitative surface roughness analysis, demonstrated that all drugs induce a substantial increase of surface roughness to an extent that correlates with the localization of the target (i.e., synthesis of mycolic acids, arabinogalactans, or proteins). Chemical force microscopy with hydrophobic tips revealed that the structural alterations induced by isoniazid and ethambutol were correlated with a dramatic decrease of cell surface hydrophobicity, reflecting the removal of the outermost mycolic acid layer. Consistent with this finding, tapping mode imaging, combined with immunogold labeling, showed that the two drugs lead to the massive exposure of hydrophilic lipoarabinomannans at the surface. Taken together, these structural, chemical, and immunological data provide novel insight into the action mode of antimycobacterial drugs, as well as into the spatial organization of the mycobacterial cell wall.

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Section: Structural Changes Correlate With Differences In Chemical Prsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Organization of the mycobacterial cell wall: a nanoscale view

Alsteens

Verbelen

Dague

et al. 2007

Pflugers Arch - Eur J Physiol

109

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“…By inhibiting arabinogalactan synthesis, EMB prevents formation of its covalently-bound mycolate layer. 11,12,27,31) The visible effects of EMB on mycolate-layer formation were observed mainly at cell division planes and cell poles (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…10) Biochemical studies show that Emb proteins are arabinofuranosyl transferases. [11][12][13] Some discrepancies remain, in that disruption of any one emb gene is not lethal. 12) C. glutamicum has a cell-wall structure and composition similar to mycobacteria: the cytoplasmic membrane is covered with a thick peptidoglycan layer, and an arabinogalactan layer surrounds the peptiodoglycan.…”

mentioning

confidence: 99%

Fluorescent Phospholipid Analogs as Microscopic Probes for Detection of the Mycolic Acid-Containing Layer inCorynebacterium glutamicum: Detecting Alterations in the Mycolic Acid-Containing Layer Following Ethambutol Treatment

Kumagai

Hirasawa

Hayakawa

et al. 2005

Bioscience, Biotechnology, and Biochemistry

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“…Comparison with the reference strain showed four mutations: three non-synonymous substitutions and one silent mutation. The closest match found in public databases was with the embRAB genes of a moderately ethambutol-resistant M. avium strain (GenBank accession number U66560) (Belanger et al, 1996) (99 % identity, 3211/3213 nt). Comparison to the latter strain revealed two new mutations: one synonymous silent mutation and one non-synonymous.…”

Section: Dna Sequencing Of the Ethambutol Target Genementioning

confidence: 99%

Molecular characterization and drug susceptibility profile of a Mycobacterium avium subspecies avium isolate from a dog with disseminated infection

Armas

Furlanello²,

Camperio

et al. 2016

Journal of Medical Microbiology

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Mycobacterium avium-intracellulare complex (MAC) infections have been described in many mammalian species, including humans and pets. We isolated and molecularly typed the causative agent of a rare case of disseminated mycobacteriosis in a dog. We identified the pathogen as M. avium subspecies avium by sequencing the partial genes gyrB and rpsA. Considering the zoonotic potential of this infection, and in an attempt to ensure the most effective treatment for the animal, we also determined the drug susceptibility profile of the isolate to the most common drugs used to treat MAC disease in humans. The pathogen was tested in vitro against the macrolide clarithromycin, as well as against amikacin, ciprofloxacin, rifampicin, ethambutol and linezolid, by the resazurin microdilution assay. It was found to be sensitive to all tested drugs apart from ethambutol. Despite the fact that the pathogen was sensitive to the therapies administered, the dog's overall clinical status worsened and the animal died shortly after antimicrobial susceptibility results became available. Nucleotide sequencing of the embB gene, the target gene most commonly associated with ethambutol resistance, showed new missense mutations when compared to sequences available in public databases. In conclusion, we molecularly identified the MAC pathogen and determined its drug susceptibility profile in a relatively short period of time (7 days). We also characterized new genetic mutations likely to have been involved in the observed ethambutol resistance. Our results confirmed the usefulness of both the gyrB and the rpsA genes as biomarkers for an accurate identification and differentiation of MAC pathogens.

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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-

Cited by 404 publications

References 30 publications

Organization of the mycobacterial cell wall: a nanoscale view

Organization of the mycobacterial cell wall: a nanoscale view

Fluorescent Phospholipid Analogs as Microscopic Probes for Detection of the Mycolic Acid-Containing Layer inCorynebacterium glutamicum: Detecting Alterations in the Mycolic Acid-Containing Layer Following Ethambutol Treatment

Molecular characterization and drug susceptibility profile of a Mycobacterium avium subspecies avium isolate from a dog with disseminated infection

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