Effect of Ethambutol on Nucleic Acid Metabolism in
            <i>Mycobacterium smegmatis</i>
            and Its Reversal by Polyamines and Divalent Cations

Forbes, M.; Kuck, N. A.; Peets, Edwin A.

doi:10.1128/jb.89.5.1299-1305.1965

Cited by 58 publications

(8 citation statements)

References 14 publications

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“…2, we propose that the inhibition of arabinan synthesis by ethambutol, and the resulting accumulation of decaprenyl-phospho-arabinose [32,33], could have further repercussions via a feedback mechanism, and inhibit, directly or indirectly, the PRPP synthetase activity in mycobacteria. This would result in decreased amounts of the PRPP precursor and, in agreement with the observed complex effects of the drug, lead to the inhibition of the synthesis of decaprenyl-phospho-ribose [32,33], but also of nucleic acids and other compounds [54].…”

Section: Formation Of 5-phosphoribosyl-a-1-pyrophosphatementioning

confidence: 78%

Biosynthesis of D‐arabinose in mycobacteria – a novel bacterial pathway with implications for antimycobacterial therapy

2008

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Decaprenyl-phospho-arabinose (b-d-arabinofuranosyl-1-O-monophosphodecaprenol), the only known donor of d-arabinose in bacteria, and its precursor, decaprenyl-phospho-ribose (b-d-ribofuranosyl-1-O-monophosphodecaprenol), were first described in 1992. En route to d-arabinofuranose, the decaprenyl-phospho-ribose 2¢-epimerase converts decaprenyl-phospho-ribose to decaprenyl-phospho-arabinose, which is a substrate for arabinosyltransferases in the synthesis of the cell-wall arabinogalactan and lipoarabinomannan polysaccharides of mycobacteria. The first step of the proposed decaprenylphospho-arabinose biosynthesis pathway in Mycobacterium tuberculosis and related actinobacteria is the formation of d-ribose 5-phosphate from sedoheptulose 7-phosphate, catalysed by the Rv1449 transketolase, and ⁄ or the isomerization of d-ribulose 5-phosphate, catalysed by the Rv2465 d-ribose 5-phosphate isomerase. d-Ribose 5-phosphate is a substrate for the Rv1017 phosphoribosyl pyrophosphate synthetase which forms 5-phosphoribosyl 1-pyrophosphate (PRPP). The activated 5-phosphoribofuranosyl residue of PRPP is transferred by the Rv3806 5-phosphoribosyltransferase to decaprenyl phosphate, thus forming 5¢-phosphoribosyl-monophospho-decaprenol. The dephosphorylation of 5¢-phosphoribosyl-monophospho-decaprenol to decaprenyl-phospho-ribose by the putative Rv3807 phospholipid phosphatase is the committed step of the pathway. A subsequent 2¢-epimerization of decaprenyl-phospho-ribose by the heteromeric Rv3790 ⁄ Rv3791 2¢-epimerase leads to the formation of the decaprenyl-phospho-arabinose precursor for the synthesis of the cell-wall arabinans in Actinomycetales. The mycobacterial 2¢-epimerase Rv3790 subunit is similar to the fungal d-arabinono-1,4-lactone oxidase, the last enzyme in the biosynthesis of d-erythroascorbic acid, thus pointing to an evolutionary link between the d-arabinofuranose-and l-ascorbic acidrelated pathways. Decaprenyl-phospho-arabinose has been a lead compound for the chemical synthesis of substrates for mycobacterial arabinosyltransferases and of new inhibitors and potential antituberculosis drugs. The peculiar (x,mono-E,octa-Z) configuration of decaprenol has yielded insights into lipid biosynthesis, and has led to the identification of the novel Z-polyprenyl diphosphate synthases of mycobacteria. Mass spectrometric methods were developed for the analysis of anomeric linkages and of dolichol phosphaterelated lipids. In the field of immunology, the renaissance in mycobacterial polyisoprenoid research has led to the identification of mimetic mannosyl-b-1-phosphomycoketides of pathogenic mycobacteria as potent lipid antigens presented by CD1c proteins to human T cells.Abbreviations ALO, D-arabinono-1,4-lactone oxidase; Araf, D-arabinofuranose; GLO, L-gulono-1,4-lactone oxidase; PRPP, 5-phosphoribosyl 1-pyrophosphate.

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Section: Formation Of 5-phosphoribosyl-a-1-pyrophosphatementioning

confidence: 78%

Biosynthesis of D‐arabinose in mycobacteria – a novel bacterial pathway with implications for antimycobacterial therapy

2008

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“…EMB is a very specific and effective drug that is used in combination with INH to treat M. tuberculosis infection (76,80,160,171). The molecular mechanism of EMB action is unknown, but experimental data have been generated and several hypotheses have been advanced to explain its action (9,26,44,45,73,84,88,123,125,128,143,153,154). Most of the data have been generated from study of the effects of EMB on mycobacterial species other than M. tuberculosis.…”

Section: Ethambutolmentioning

confidence: 99%

“…Most of the data have been generated from study of the effects of EMB on mycobacterial species other than M. tuberculosis. Among the effects attributed to EMB are inhibition of RNA metabolism (44,45), phospholipid synthesis (26,84), transfer of mycolic acids to cell wall-linked arabinogalactan (153), spermidine synthesis (123,125), and an early step of glucose conversion into the monosaccharides used for the cell wall polysaccharides arabinogalactan, aribinomannan, and peptidoglycan (143). Thus far, no genes known to encode products participating in EMB resistance have been described.…”

Section: Ethambutolmentioning

confidence: 99%

Antimicrobial agent resistance in mycobacteria: molecular genetic insights

1995

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The primary theme emerging from molecular genetic work conducted with Mycobacterium tuberculosis and several other mycobacterial species is that resistance is commonly associated with simple nucleotide alterations in target chromosomal genes rather than with acquisition of new genetic elements encoding antibiotic-altering enzymes. Mutations in an 81-bp region of the gene (rpoB) encoding the beta subunit of RNA polymerase account for rifampin resistance in 96% of M. tuberculosis and many Mycobacterium leprae isolates. Streptomycin resistance in about one-half of M. tuberculosis isolates is associated with missense mutations in the rpsL gene coding for ribosomal protein S12 or nucleotide substitutions in the 16S rRNA gene (rrs). Mutations in the katG gene resulting in catalase-peroxidase amino acid alterations nad nucleotide substitutions in the presumed regulatory region of the inhA locus are repeatedly associated with isoniazid-resistant M. tuberculosis isolates. A majority of fluoroquinolone-resistant M. tuberculosis isolates have amino acid substitutions in a region of the DNA gyrase A subunit homologous to a conserved fluoroquinolone resistance-determining region. Multidrug-resistant isolates of M. tuberculosis arise as a consequence of sequential accumulation of mutations conferring resistance to single therapeutic agents. Molecular strategies show considerable promise for rapid detection of mutations associated with antimicrobial resistance. These approaches are now amenable to utilization in an appropriately equipped clinical microbiology laboratory.

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“…Although several hypotheses have been advanced to explain the mechanism of action of EMB, most studies have implicated a detrimental alteration of the mycobacterial cell wall structure (1,7,9,16,20,28,29,32,38). Takayama and Kilburn (32) showed that EMB inhibited the transfer of arabinogalactan into the cell wall of Mycobacterium smegmatis, a process that led to the accumulation of trehalose mono-and dimycolates in the medium.…”

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confidence: 99%

Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations

Sreevatsan

Stockbauer

Pan

et al. 1997

Antimicrob Agents Chemother

275

109

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Ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB], is a first-line drug used to treat tuberculosis. To gain insight into the molecular basis of EMB resistance, we characterized the 10-kb embCAB locus in 16 EMB-resistant and 3 EMB-susceptible genetically distinct Mycobacterium tuberculosis strains from diverse localities by automated DNA sequencing and single-stranded conformation polymorphism analysis. All 19 organisms had virtually identical sequences for the entire 10-kb region. Eight EMB-resistant organisms had mutations located in codon 306 of embB that resulted in the replacement of the wild-type Met residue with Ile or Val. Automated sequence analysis of the 5' region (1,892 bp) of embB in an additional 69 EMB-resistant and 30 EMB-susceptible M. tuberculosis isolates from diverse geographic localities and representing 70 distinct IS6110 fingerprints confirmed the unique association of substitutions in amino acid residue 306 of EmbB with EMB resistance. Six other embB nucleotide substitutions resulting in four amino acid replacements were uniquely found in resistant strains. Sixty-nine percent of epidemiologically unassociated EMB-resistant organisms had an amino acid substitution not found in susceptible strains, and most (89%) replacements occurred at amino acid residue 306 of EmbB. For strains with the Met306Leu or Met306Val replacements EMB MICs were generally higher (40 microg/ml) than those for organisms with Met306Ile substitutions (20 microg/ml). The data are consistent with the idea that amino acid substitutions in EmbB alter the drug-protein interaction and thereby cause EMB resistance.

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Effect of Ethambutol on Nucleic Acid Metabolism in Mycobacterium smegmatis and Its Reversal by Polyamines and Divalent Cations

Cited by 58 publications

References 14 publications

Biosynthesis of D‐arabinose in mycobacteria – a novel bacterial pathway with implications for antimycobacterial therapy

Biosynthesis of D‐arabinose in mycobacteria – a novel bacterial pathway with implications for antimycobacterial therapy

Antimicrobial agent resistance in mycobacteria: molecular genetic insights

Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations

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