Friulimicins. Novel Lipopeptide Antibiotics with Peptidoglycan Synthesis Inhibiting Activity from Actinoplanes friuliensis sp. nov. II. Isolation and Structural Characterization.

Vértesy, László; Ehlers, Eberhard; Kogler, Herbert; Kurz, Michael; Meiwes, Johannes; Seibert, Gerhard; Vögel, Martin; Hammann, Peter

doi:10.7164/antibiotics.53.816

Cited by 102 publications

(85 citation statements)

References 18 publications

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“…42 This antibiotic complex consists of a highly conserved side-chain-cyclized undecapeptide portion that is acylated by one variable unsaturated and branched (iso or anteiso) fatty acid moiety. The complete structural identity of the fatty acid substituent was determined very recently by Vertesy et al, 43 and turned out to be (Z -anteiso-3-tridecenoic acid (amfomycin A 1 ).…”

Section: Amfomycin (Amphomycin)mentioning

confidence: 97%

Comparison of CID spectra of singly charged polypeptide antibiotic precursor ions obtained by positive‐ion vacuum MALDI IT/RTOF and TOF/RTOF, AP‐MALDI‐IT and ESI‐IT mass spectrometry

et al. 2006

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Various classes of polypeptide antibiotics, including blocked linear peptides (gramicidin D), side-chaincyclized peptides (bacitracin, viomycin, capreomycin), side-chain-cyclized depsipeptides (virginiamycin S), real cyclic peptides (tyrocidin, gramcidin S) and side-chain-cyclized lipopeptides (polymyxin B and E, amfomycin), were investigated by low-energy collision induced dissociation (LE-CID) as well as highenergy CID (HE-CID). Ion trap (IT) based instruments with different desorption/ionization techniques such as electrospray ionization (ESI), atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI) and vacuum MALDI (vMALDI) as well as a vMALDI-time-of-flight (TOF)/curved fieldreflectron instrument fitted with a gas collision cell were used. For optimum comparability of data from different IT instruments, the CID conditions were standardized and only singly charged precursor ions were considered. Additionally, HE-CID data obtained from the TOF-based instrument were acquired and compared with LE-CID data from ITs. Major differences between trap-based and TOF-based CID data are that the latter data set lacks abundant additional loss of small neutrals (e.g. ammonia, water) but contains product ions down to the immonium-ion-type region, thereby allowing the detection of even single amino-acid (even unusual amino acids) substitutions. For several polypeptide antibiotics, mass spectrometric as well as tandem mass spectrometric data are shown and discussed for the first time, and some yet undescribed minor components are also reported. De novo sequencing of unusually linked minor components of (e.g. cyclic) polypeptides is practically impossible without knowledge of the exact structure and fragmentation behavior of the major components. Finally, the described standardized CID condition constitutes a basic prerequisite for creating a searchable, annotated MS n -database of bioactive compounds. The applied desorption/ionization techniques showed no significant influence on the type of product ions (neglecting relative abundances of product ions formed) observed, and therefore the type of analyzer connected with the CID process mainly determines the type of fragment ions.

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Section: Amfomycin (Amphomycin)mentioning

confidence: 97%

Comparison of CID spectra of singly charged polypeptide antibiotic precursor ions obtained by positive‐ion vacuum MALDI IT/RTOF and TOF/RTOF, AP‐MALDI‐IT and ESI‐IT mass spectrometry

et al. 2006

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“…The structures of four of these lipopeptides are identical to those of known peptide antibiotics of the amphomycin group and possess aspartic acid at the exocyclic position. The other four lipopeptides have asparagine at this position and are known as friulimicins A to D. The peptide component of these friulimicins is characterized by unusual amino acids, such as L-threo-and D-erythro-2,3-diaminobutyric acid, D-pipecolinic acid, and L-threo-␤-methylaspartic acid (48) (Fig. 1).…”

mentioning

confidence: 99%

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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“…Both compounds are inhibitors of the mitochondrial respiratory energy metabolism (Sasse et al, 2003 (Vertesy et al, 2000).The lipopeptide antibiotic friulimicin A-D, produced by Actinoplanes friuliensis, is an effective drug against Gram-positive bacteria, such as methicillinresistant Staphylococcus epidermidis and S. aureus strains. Friulimicin consisting of the acyl residue is essential for antibiotic activity; however, it varies in length from C13 to C15, and carries a characteristic double bond at position  cis-3.…”

Section: Branched Saturated and Unsaturated Fatty Acidsmentioning

confidence: 99%

“…Four of the eight lipopeptides (A1437 A, A1437 B, A1437 E, A1437 G) have aspartate as the exocyclic amino acid and are identical to known peptide antibiotics of the amphomycin group. The other four lipopeptide structures (friulimicin A-D) have asparagine as the exocyclic amino acid and represent a new class of antibiotics (Vertesy et al, 2000 (Hammann et al, 2001). …”

Section: Branched Saturated and Unsaturated Fatty Acidsmentioning

confidence: 99%

Paradigm Shifts in Fungal Secondary Metabolite Research: Unusual Fatty Acids Incorporated into Fungal Peptides

Dembitsky¹

2017

Int. J. Curr. Res. Biosci. Plant Biol.

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A b s t r a c t A r t i c l e I n f oThis review is a comprehensive survey of unique, unusual, and rare fatty acids incorporated into natural marine and terrestrial peptides obtained from fungi, fungal endophytes, lichenized ascomycetes, basidiomycetes, and actinomycetes. Lots of fungal peptides display important biological activities of interest, which includes antitumor, antibacterial, antimicrobial, antifungal, phototoxic, HIV inhibitory, immunosuppressive properties, and other pharmacological activities. There is no doubt that they are of great importance, especially in medicinal chemistry and/or pharmaceutical application. This review presents structures of more than 150 fatty acids, incorporated into marine and terrestrial fungal lipopeptides.

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Friulimicins. Novel Lipopeptide Antibiotics with Peptidoglycan Synthesis Inhibiting Activity from Actinoplanes friuliensis sp. nov. II. Isolation and Structural Characterization.

Cited by 102 publications

References 18 publications

Comparison of CID spectra of singly charged polypeptide antibiotic precursor ions obtained by positive‐ion vacuum MALDI IT/RTOF and TOF/RTOF, AP‐MALDI‐IT and ESI‐IT mass spectrometry

Comparison of CID spectra of singly charged polypeptide antibiotic precursor ions obtained by positive‐ion vacuum MALDI IT/RTOF and TOF/RTOF, AP‐MALDI‐IT and ESI‐IT mass spectrometry

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

Paradigm Shifts in Fungal Secondary Metabolite Research: Unusual Fatty Acids Incorporated into Fungal Peptides

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