A21978C, a complex of new acidic peptide antibiotics. Isolation, chemistry, and mass spectral structure elucidation.

Debono, Manuel; Barnhart, M.; Carrell, Claude B.; Hoffmann, J. A.; Occolowitz, John L.; Abbott, Bernard J.; Fukuda, D. S.; Hamill, Robert L.; Biemann, K.; Herlihy, Walter C.

doi:10.7164/antibiotics.40.761

Cited by 191 publications

(167 citation statements)

References 15 publications

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“…The C-terminal ten amino acids form a macrocyclic core, which contains a ring-closing depsi (ester) bond between the side chain of Thr (4) and the α-COOH of the C-terminal Kyn (13) . 23,24 The N-terminal tripeptide protrudes from the ring and carries the variable fatty acyl residue, which is attached to Trp (1) .…”

Section: Structure and Biosynthesismentioning

confidence: 99%

“…Removal of the lipid results in complete loss of biological activity, as did the hydrolysis of the ring-closing ester bond. 23 Semisynthetic n-acyl variants showed antimicrobial activity increasing with the length of the acyl chain up to ten carbons. Beyond this length, in vitro activity increased with some, but not other bacterial strains; in vivo activity showed no further improvement.…”

Section: Role Of the Fatty Acyl Tailmentioning

confidence: 99%

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The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

237

172

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Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Streptomyces roseosporus that is clinically used to treat severe infections with Grampositive bacteria. In this review, we discuss the mode of action of this important antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimental studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This activity, which can account for daptomycin's bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial resistance to daptomycin. While other resistance mechanisms suggest that daptomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin's complex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space.

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Section: Structure and Biosynthesismentioning

confidence: 99%

Section: Role Of the Fatty Acyl Tailmentioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

237

172

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“…It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. 8,9 We have also found a novel anti-MRSA antibiotic, WAP-8294A, that is a complex of 20 closely related components produced by Lysobacter sp. 10 The WAP-8294A2 (1) was isolated as the major component, while A1 (2), A4 (3) and Ax13 (4) were minor components.…”

Section: Introductionmentioning

confidence: 95%

A new anti-MRSA antibiotic complex, WAP-8294A II. Structure characterization of minor components by ESI LCMS and MS/MS

Kato

Hirata

Ohashi³

et al. 2011

J Antibiot

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The anti-MRSA antibiotic, WAP-8294A, was isolated from the fermentation broth of Lysobacter sp. The major component,and 2 mol of L-Ser, D-Orn and D-3-hydroxy-7-Me-octanoic acid. The structure of the WAP-8294A2 was mainly determined as a cyclic depsipeptide by 2D NMR experiments. However, it was difficult to use the NMR experiment to determine the minor components, A1, A4 and Ax13, isolated in small amounts. In the present study, ESI MS/MS was applied to the structure elucidation of these minor components. The structures of these minor components were determined on the basis of the fragmentation pattern of the product ions of WAP-8294A2 in the ESI MS/MS. As a result, it was confirmed that A1 and A4 had the same amino acid sequence as A2, while A1 and A4 had the 3-OH-octanoic acid and 3-OH-8-Me-nonanoic acid, respectively, in the place of the 3-OH-7-Meoctanoic acid in A2. In the structure of Ax13, it was found that Gly of A2 was changed to b-Ala of Ax13.

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“…A21978C ( Figure 1) was discovered by Eli Lilly and Company, 5 and daptomycin is a semisynthetic derivative of A21978C containing a decanoic acid side chain rather than the natural lipid side chains of A21978C factors. 6 Daptomycin was licensed from Lilly to Cubist Pharmaceuticals 7 , and has been approved for the treatment of difficult-to-treat skin and skin structure infections caused by Gram-positive pathogens, 8 and for bacteremia and right-sided endocarditis caused by Staphylococcus aureus, including strains resistant to methicillin (MRSA (methicillin-resistant S. aureus)).…”

Section: Introductionmentioning

confidence: 99%

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

Baltz¹

2010

J Antibiot

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Daptomycin is a clinically useful lipopeptide antibiotic produced by Streptomyces roseosporus. The antibiotic is assembled by a nonribosomal peptide synthetase (NRPS) mechanism, and the cyclized tridecapeptide contains three non-proteinogenic L-amino acids: ornithine (Orn), 3-methyl-glutamic acid (3mGlu) and kynurinine (Kyn). Daptomycin also has three D-amino acids. The two genes that encode proteins involved in the formation of 3mGlu and Kyn have no known orthologs, and hence they are good probes to search for daptomycin-like gene clusters among newly sequenced actinomycete genomes. A recent search with these genes revealed a daptomycin-like gene cluster in Saccharomonospora viridis, a causative agent for farmer's lung disease. S. viridis has a genome of 4.3 Mb, which is about one half the size of Streptomyces genomes. Searches for other NRPS and polyketide synthase (PKS) genes revealed only one other NRPS gene and no PKS genes in S. viridis. The orthologous lipopeptide biosynthetic genes and gene products in S. viridis and S. roseosporus have diverged extensively from a last common ancestor dating back to a pathway that had evolved over 1 billion years ago.

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A21978C, a complex of new acidic peptide antibiotics. Isolation, chemistry, and mass spectral structure elucidation.

Cited by 191 publications

References 15 publications

The action mechanism of daptomycin

The action mechanism of daptomycin

A new anti-MRSA antibiotic complex, WAP-8294A II. Structure characterization of minor components by ESI LCMS and MS/MS

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

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