STEREOSPECIFICITY IN A NEW TYPE OF SYNTHETIC ANTITUBERCULOUS AGENT<sup>1,2</sup>

Wilkinson, R. G.; Shepherd, R. G.; Thomas, John P.; Baughn, Caroline

doi:10.1021/ja01470a052

Cited by 117 publications

(39 citation statements)

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“…The mechanism of action and the molecular genetic basis of resistance to EMB are not fully understood. Only the dextro isomer of EMB is biologically active, an observation consistent with the idea that the drug binds to a specific cellular target (7,37). Several studies have implicated membrane-associated arabinosyltransferases as targets for EMB (1,5,20,22).…”

Section: Ethambutol [Emb; (S S)-22ј-(ethylenediimino)di-1-buta-supporting

confidence: 66%

Molecular Genetic Analysis of Nucleotide Polymorphisms Associated with Ethambutol Resistance in Human Isolates of Mycobacterium tuberculosis

Ramaswamy

Amin

Göksel

et al. 2000

Antimicrob Agents Chemother

223

216

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Ethambutol (EMB) is a central component of drug regimens used worldwide for the treatment of tuberculosis. To gain insight into the molecular genetic basis of EMB resistance, approximately 2 Mb of five chromosomal regions with 12 genes in 75 epidemiologically unassociated EMB-resistant and 33 EMB-susceptibleMycobacterium tuberculosis strains isolated from human patients were sequenced. Seventy-six percent of EMBresistant organisms had an amino acid replacement or other molecular change not found in EMB-susceptible strains. Thirty-eight (51%) EMB-resistant isolates had a resistance-associated mutation in only 1 of the 12 genes sequenced. Nineteen EMB-resistant isolates had resistance-associated nucleotide changes that conferred amino acid replacements or upstream potential regulatory region mutations in two or more genes. Most isolates (68%) with resistance-associated mutations in a single gene had nucleotide changes in embB, a gene encoding an arabinosyltransferase involved in cell wall biosynthesis. The majority of these mutations resulted in amino acid replacements at position 306 or 406 of EmbB. Resistance-associated mutations were also identified in several genes recently shown to be upregulated in response to exposure of M. tuberculosis to EMB in vitro, including genes in the iniA operon. Approximately one-fourth of the organisms studied lacked mutations inferred to participate in EMB resistance, a result indicating that one or more genes that mediate resistance to this drug remain to be discovered. Taken together, the results indicate that there are multiple molecular pathways to the EMB resistance phenotype. Ethambutol [EMB; (S, S)-2,2Ј-(ethylenediimino)di-1-buta-nol] is used worldwide as one of the primary antituberculosis agents. The mechanism of action and the molecular genetic basis of resistance to EMB are not fully understood. Only the dextro isomer of EMB is biologically active, an observation consistent with the idea that the drug binds to a specific cellular target (7, 37). Several studies have implicated membrane-associated arabinosyltransferases as targets for EMB (1,5,20,22). These enzymes are well conserved in mycobacteria and are involved in the biosynthesis of arabinan, a component of arabinogalactan present in cell walls (6,8,17,33,34,39). Inhibition of arabinan synthesis leads to accumulation of mycolic acids and eventually to cell death.Three contiguous genes encoding arabinosyltransferases and designated embC, embA, and embB have been identified in Mycobacterium tuberculosis (35). The proteins encoded by these genes are about 65% identical to each other. Previous studies based on limited sequencing of the 10-kb region containing the embCAB genes have identified mutations that result in replacement of amino acid residues and are found only in EMB-resistant organisms cultured from humans. The most commonly affected amino acid was Met306 of EmbB. For example, Sreevatsan et al. (31) identified five distinct mutant codons that resulted in replacement of wild-type Met306 with Ile, Leu, or Va...

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Section: Ethambutol [Emb; (S S)-22ј-(ethylenediimino)di-1-buta-supporting

confidence: 66%

Molecular Genetic Analysis of Nucleotide Polymorphisms Associated with Ethambutol Resistance in Human Isolates of Mycobacterium tuberculosis

Ramaswamy

Amin

Göksel

et al. 2000

Antimicrob Agents Chemother

223

216

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“…A ligand that fulfills these requisites is ethambutol. This molecule was already used in medicine as an anti-tuberculosis, and very interestingly, only the S,S isomer was found very active; the R,R enantiomer was completely inactive (26,27). Starting with an isomerically pure ligand, coordination to platinum leads to formation of different isomers.…”

Section: Platinum Complexes With Chiral N-substituted Ethylenediaminesmentioning

confidence: 99%

Chiral discrimination in platinum anticancer drugs.

Benedetti

Malina

Kašpárková

et al. 2002

Environ Health Perspect

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In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

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“…This compound, melting at 473 K, shows an enantiotropic phase transition at 343 K that is reversible by cooling (Kuhnert-Brandst~itter & Moser, 1979). (R,S)-2,2'-(1,2-Ethanediyldiimino)bis-l-butanol dihydrochloride (RSET) was synthesized according to Wilkinson, Shepherd, Thomas & Baughn (1961). (RSET) shows a phase transition at 313 K analogous to (SSET).…”

Section: (Rs)-nn'-bis( L-hydroxymethylpropyl)-mentioning

confidence: 99%

The structures of (R,S)-2,2'-(1,2-ethanediyldiimino)bis-1-butanol dihydrochloride at 295 and 333 K. A reversible phase transition

Sorensen¹,

Simonsen²

1989

Acta Crystallogr C

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STEREOSPECIFICITY IN A NEW TYPE OF SYNTHETIC ANTITUBERCULOUS AGENT^1,2

Cited by 117 publications

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Molecular Genetic Analysis of Nucleotide Polymorphisms Associated with Ethambutol Resistance in Human Isolates of Mycobacterium tuberculosis

Molecular Genetic Analysis of Nucleotide Polymorphisms Associated with Ethambutol Resistance in Human Isolates of Mycobacterium tuberculosis

Chiral discrimination in platinum anticancer drugs.

The structures of (R,S)-2,2'-(1,2-ethanediyldiimino)bis-1-butanol dihydrochloride at 295 and 333 K. A reversible phase transition

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STEREOSPECIFICITY IN A NEW TYPE OF SYNTHETIC ANTITUBERCULOUS AGENT1,2

Cited by 117 publications

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Molecular Genetic Analysis of Nucleotide Polymorphisms Associated with Ethambutol Resistance in Human Isolates of Mycobacterium tuberculosis

Molecular Genetic Analysis of Nucleotide Polymorphisms Associated with Ethambutol Resistance in Human Isolates of Mycobacterium tuberculosis

Chiral discrimination in platinum anticancer drugs.

The structures of (R,S)-2,2'-(1,2-ethanediyldiimino)bis-1-butanol dihydrochloride at 295 and 333 K. A reversible phase transition

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STEREOSPECIFICITY IN A NEW TYPE OF SYNTHETIC ANTITUBERCULOUS AGENT^1,2