The Structure of Fatty Acids From the Antibiotic Amphomycin

Bodanszky, Miklos; Chaturvedi, N. C.; Scozzie, James A.

doi:10.7164/antibiotics.22.399

Cited by 12 publications

(6 citation statements)

References 3 publications

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“…Epimerization domains are located at the ends of PstB and PstC in the modules 3 and 9, in accordance with the D configuration of pipecolinic acid and the Dab-9 amino acid residue. This result is consistent with the published stereochemical structure of the friulimicin and amphomycin peptides (7,48). PstD ends with a thioesterase domain for regiospecific cyclization.…”

Section: Resultssupporting

confidence: 81%

Sequencing and Analysis of the Biosynthetic Gene Cluster of the Lipopeptide Antibiotic Friulimicin in Actinoplanes friuliensis

Müller

Nolden

Gebhardt

et al. 2007

Antimicrob Agents Chemother

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Actinoplanes friuliensis produces the lipopeptide antibiotic friulimicin, which is a cyclic peptide with one exocyclic amino acid linked to a branched-chain fatty acid acyl residue. The structural relationship to daptomycin and the excellent antibacterial performance of friulimicin make the antibiotic an attractive drug candidate. The complete friulimicin biosynthetic gene cluster of 24 open reading frames from A. friuliensis was sequenced and analyzed. In addition to genes for regulation, self-resistance, and transport, the cluster contains genes encoding peptide synthetases, proteins involved in the synthesis and linkage of the fatty acid component of the antibiotic, and proteins involved in the synthesis of the nonproteinogenic amino acids pipecolinic acid, methylaspartic acid, and 2,3-diaminobutyric acid. By using heterologous gene expression in Escherichia coli, we provide biochemical evidence for the stereoselective synthesis of L-pipecolinic acid by the deduced protein of the lysine cyclodeaminase gene pip. Furthermore, we show the involvement of the dabA and dabB genes in the biosynthesis of 2,3-diaminobutyric acid by gene inactivation and subsequent feeding experiments.In recent years, the sequences of numerous gene clusters involved in the synthesis of many secondary metabolites have become available for comparison and exploitation. The programmed manipulation of genes encoding enzymes in the biosynthetic pathways offers promise for redesigning existing antibiotic structures to create antibiotics with new activities and the ability to overcome bacterial resistance (50). Therefore, each newly analyzed gene cluster represents a new tool for combinatorial biosynthesis and can provide information about the synthesis of unusual building blocks, such as nonproteinogenic amino acids, acyl residues, and sugar moieties. An interesting group of secondary metabolites for such experiments seems to be bioactive lipopeptides isolated from streptomycetes. So far, only a few biosynthetic gene clusters corresponding to these lipopeptides have been isolated and characterized, such as the clusters for calcium-dependent antibiotic (CDA) from Streptomyces coelicolor (17), daptomycin from Streptomyces roseosporus (26), and A54145 from Streptomyces fradiae (24). By targeted modification and gene exchange, it is possible to generate new lipopeptide structures (12,25).Another member of this group of secondary metabolites is the antibiotic friulimicin that is produced by the actinomycete Actinoplanes friuliensis. This compound is highly active against multidrug-resistant gram-positive bacteria, such as methicillinresistant Staphylococcus aureus strains (4). The biosynthesis of this lipopeptide is catalyzed by nonribosomal peptide synthetases (NRPS) (15).The eight bioactive lipopeptides isolated from A. friuliensis (4) consist of 10 amino acids that form a ring structure with one exocyclic amino acid linked to an acyl residue of various chain lengths. The acyl residue is a branched-chain fatty acid with a ⌬cis3 double bond. The ...

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Section: Resultssupporting

confidence: 81%

Sequencing and Analysis of the Biosynthetic Gene Cluster of the Lipopeptide Antibiotic Friulimicin in Actinoplanes friuliensis

Müller

Nolden

Gebhardt

et al. 2007

Antimicrob Agents Chemother

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“…From acid hydrolysates of amphomycin, L-aspartic acid (3 mol), glycine (2 mol), L-rftreo-/3-methylaspartic acid,17 L-proline, L-valine, dpipecolic acid, w/z/-eo-a,/3-diaminobutyric acid,18 and D-eryí/iro-a,/3-diaminobutyric acid16 (1 mol each) were isolated and identified. 16 End Groups. Rearrangements.…”

Section: Methodsmentioning

confidence: 99%

Structure of the peptide antibiotic amphomycin

Bodanszky¹,

Sigler²,

Bodánszky³

1973

J. Am. Chem. Soc.

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“…24, 25 Subsequent studies of the structure of amphomycin indicated that its fatty acid and amino acid constituents were identical to those of glumamycin, and that aspartocin had the same amino acid content but different fatty acyl substituents. [45][46][47][48][49] This resulted in a proposal that most of the individual members of the amphomycin family contained the same amino acids in identical ratios and differed only in respect of their fatty acid constituents, which should be regarded as merely a consequence of the fermentation media and conditions used for their production. Complications in chromatographic characterization could also have arisen from facile transpeptidation reactions yielding b-aspartyl isomers due to the proximity of Gly and Asp residues in these molecules.…”

Section: Cyclic Peptidesmentioning

confidence: 99%

Natural products to drugs: daptomycin and related lipopeptide antibiotics

2005

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Daptomycin (Cubicin) is a lipopeptide antibiotic approved in the USA in 2003 for the treatment of skin and skin structure infections caused by Gram-positive pathogens. It is a member of the 10-membered cyclic lipopeptide family of antibiotics that includes A54145, calcium-dependent antibiotic (CDA), amphomycin, friulimicin, laspartomycin, and others. This review highlights research on this class of antibiotics from 1953 to 2005, focusing on more recent studies with particular emphasis on the interplay between structural features and antibacterial activities; chemical modifications to improve activity; the genetic organization and biosynthesis of lipopeptides; and the genetic engineering of the daptomycin biosynthetic pathway to produce novel derivatives for further chemical modification to develop candidates for clinical evaluation.

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The Structure of Fatty Acids From the Antibiotic Amphomycin

Cited by 12 publications

References 3 publications

Sequencing and Analysis of the Biosynthetic Gene Cluster of the Lipopeptide Antibiotic Friulimicin in Actinoplanes friuliensis

Sequencing and Analysis of the Biosynthetic Gene Cluster of the Lipopeptide Antibiotic Friulimicin in Actinoplanes friuliensis

Structure of the peptide antibiotic amphomycin

Natural products to drugs: daptomycin and related lipopeptide antibiotics

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