Relation of structures and microbiological activities of the 16-membered macrolides

Ōmura, Satoshi; Tishler, Max; Nakagawa, Akira; Hironaka, Yukino; Hata, Tōju

doi:10.1021/jm00280a003

Cited by 61 publications

(15 citation statements)

References 8 publications

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“…The chalcomycins also contain a C-6(S) methyl side chain rather than the C-6(R) ethylaldehyde side chain found in compounds 3 and 4 and other clinically useful 16-membered macrolides. Reduction or removal of the aldehyde in compound 3 and other 16-membered macrolides results in significant loss of ribosome binding and potency (26). X-ray analysis has shown a reversible covalent linkage between the aldehyde of compound 3 and the 6-amino group of A-2062 (Escherichia coli numbering) in domain V of the Haloarcula marismortui ribosome (15).…”

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confidence: 99%

Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

Ward¹,

Hu²,

Schirmer³

et al. 2004

Antimicrob Agents Chemother

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Chalcomycin, a 16-membered macrolide antibiotic made by the bacterium Streptomyces bikiniensis, contains a 2,3-trans double bond and the neutral sugar D-chalcose in place of the amino sugar mycaminose found in most other 16-membered macrolides. Degenerate polyketide synthase (PKS)-specific primers were used to amplify DNA fragments from S. bikiniensis with very high identity to a unique ketosynthase domain of the tylosin PKS. The resulting amplimers were used to identify two overlapping cosmids encompassing the chm PKS. Sequencing revealed a contiguous segment of >60 kb carrying 25 putative genes for biosynthesis of the polyketide backbone, the two deoxysugars, and enzymes involved in modification of precursors of chalcomycin or resistance to it. The chm PKS lacks the ketoreductase and dehydratase domains in the seventh module expected to produce the 2,3-double bond in chalcomycin. Expression of PKS in the heterologous host Streptomyces fradiae, from which the tyl genes encoding the PKS had been removed, resulted in production of at least one novel compound, characterized as a 3-keto 16-membered macrolactone in equilibrium with its 3-trans enol tautomer and containing the sugar mycaminose at the C-5 position, in agreement with the structure predicted on the basis of the domain organization of the chm PKS. The production of a 3-keto macrolide from the chm PKS indicates that a discrete set of enzymes is responsible for the introduction of the 2,3-trans double bond in chalcomycin. From comparisons of the open reading frames to sequences in databases, a pathway for the synthesis of nucleoside diphosphate-D-chalcose was proposed.

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Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

Ward¹,

Hu²,

Schirmer³

et al. 2004

Antimicrob Agents Chemother

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“…Since a number of leucomycin analogues have been synthesized and the antibacterial activity of various derivatives have been evaluated (3)(4)(5)(6)(7), it was of interest to examine the effect of these 16-membered macrolides on both chloramphenicol and erythromycin binding to ribosomes. In addition, since leucomycins interfere with [ ]4CJerythromycin binding to ribosomes, it was possible to determine association and dissociation constants as well as interaction coefficients for each of these derivatives for binding to E. coli ribosomes, by the method previously described (1).…”

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confidence: 99%

Effect of Leucomycins and Analogues on Binding [ ¹⁴ C]Erythromycin to Escherichia coli Ribosomes

Pestka

Nakagawa

Ōmura

1974

Antimicrob Agents Chemother

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We examined the effect of leucomycins, leucomycin derivatives, and other 16-membered macrolides (tylosin, iiiddamycin, spiramycin I, and spiramycin m) on [14C]erythromycin binding to ribosomes. Results of these studies enabled determination of the association and dissociation constants for the binding of each 'of these compounds to Escherichia coli ribosomes. In addition, the binding of the leucomycins and the leucomycin derivatives to ribosomes in general correlated with their antimicrobial activity.We recently examined the effect of erythromycin and its derivatives on chloramphenicol and erythromycin binding to ribosomes from Escherichia coli (10,11 (8,9). [14Clchloramphenicol binding to ribosomes was determined in 0.05-ml reaction mixtures (Fig 2). Each reaction mixture for determination of

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“…A unique feature of the 16‐membered ring macrolides ( 41 – 43 ) has been observed with wild‐type H50S, where the aldehyde at position 6 forms a hemiaminal with the N6 exocyclic amine of A2062 25. This suggests a key role for this functionality, which is supported by the observed decreased activity of derivatives with modifications at this position in a wide variety of Gram‐positive bacteria 167,168. In addition, the saccharide moiety attached to C5 extends toward the peptidyl transferase center, which may explain why carbomycin A ( 41 ) (Figure 8) strongly inhibits formation of the first peptide bond and why tylosin and spiramycin allow the formation of very short peptides 138,165,166…”

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confidence: 84%

Transforming lives: transferring patients with neonatal diabetes from insulin to sulphonylureas

Shepherd

2006

European Diabetes Nursing

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Background: Mutations in the KCNJ11 gene encoding Kir6.2 are the most common cause of neonatal diabetes. Although clinically 'insulin dependent' these patients may respond to oral sulphonylureas. Families' experiences of coping with the condition and the impact of transferring from long-term insulin to sulphonylureas have not been explored. Aim: This study aims to increase understanding of having a child with neonatal diabetes caused by a mutation in the KCNJ11 gene. Method: In-depth interviews were conducted with parents of 11 UK patients with KCNJ11 gene mutations during 2004-2005. The patients had a median age of 13 years (range 0.5-57 years). Qualitative methodology was used to gain an in-depth understanding of the experiences from diagnosis of diabetes to present day. Interviews were audiotaped, transcribed and subjected to thematic content analysis. Results: Three key categories were identified: i) difficulties managing diabetes in a baby/young child -highlighting the constant care required and impact on family relationships; ii) recognition and implications of learning difficulties and muscle weakness; iii) impact of transfer from insulin to sulphonylureas -including effect on lifestyle, learning difficulties and glycaemic control. Conclusion: Having a baby with neonatal diabetes is exhausting and places additional strain on families. Mothers acknowledged feeling overprotective. Before genetic diagnosis learning delay and diabetes had not been related, but had implications for future independent living. Transfer to sulphonylureas greatly improved diabetes control and reduced incidences of hypoglycaemia; this enabled families to normalise the condition and reduced social stigma. Sulphonylurea treatment transformed quality of life for the children and their families, who were able to view the future more positively.Eur Diabetes Nursing 2006; 3(3): 137-142.

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Relation of structures and microbiological activities of the 16-membered macrolides

Cited by 61 publications

References 8 publications

Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

Effect of Leucomycins and Analogues on Binding [ ¹⁴ C]Erythromycin to Escherichia coli Ribosomes

Transforming lives: transferring patients with neonatal diabetes from insulin to sulphonylureas

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Relation of structures and microbiological activities of the 16-membered macrolides

Cited by 61 publications

References 8 publications

Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

Effect of Leucomycins and Analogues on Binding [ 14 C]Erythromycin to Escherichia coli Ribosomes

Transforming lives: transferring patients with neonatal diabetes from insulin to sulphonylureas

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Effect of Leucomycins and Analogues on Binding [ ¹⁴ C]Erythromycin to Escherichia coli Ribosomes