ChemInform Abstract: CONSTITUTION OF THE DEFERRIFORM OF ALBOMYCINS Δ1, Δ2, AND ε

Benz, G.; Schroeder, Thomas D.; Kurz, Jürgen; Wuensche, C. +; Karl, Wolfram; Steffens, Gerd; Pfitzner, Jörg; Schmidt, Delf

doi:10.1002/chin.198241339

Cited by 2 publications

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“…Although this specificity can be explained by the necessity of the lone pair of electrons on N4 to contribute by formation of an imine concomitant with methyl transfer, this result appears inconsistent with the isolation of albomycin δ 1 from either the wild-type or Δ abmE mutant strains. However, it was previously reported that albomycin δ 1 could be made by mild alkaline hydrolysis of albomycin δ 2 . We repeated this experiment by incubating albomycin δ 2 in 50 mM Tris-HCl pH 9 for 3 h at 37 °C.…”

Section: Resultsmentioning

confidence: 99%

Biosynthesis of Albomycin δ₂ Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates

et al. 2012

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“Trojan horse” antibiotic albomycins are peptidyl nucleosides consisting of a highly modified 4′-thiofuranosyl cytosine moiety and a ferrichrome siderophore that are linked by a peptide bond via a serine residue. While the latter component serves to sequester iron from the environment, the seryl nucleoside portion is a potent inhibitor of bacterial seryl-tRNA synthetases, resulting in broad-spectrum antimicrobial activities of albomycin δ2. The isolation of albomycins has revealed this biological activity is only optimized following two unusual cytosine modifications, N4-carbamoylation and N3-methylation. We identified a genetic locus (named abm) for albomycin production in Streptomyces sp. ATCC 700974. Gene deletion and complementation experiments along with bioinformatic analysis suggested 18 genes are responsible for albomycin biosynthesis and resistance, allowing us to propose a potential biosynthetic pathway for installing the novel chemical features. The gene abmI, encoding a putative methyltransferase, was functionally assigned in vitro and shown to modify the N3 of a variety of cytosine-containing nucleosides and antibiotics such as blasticidin S. Furthermore, a ΔabmI mutant was shown to produce the descarbamoyl-desmethyl albomycin analog, supporting that the N3-methylation occurs before the N4-carbamoylation in the biosynthesis of albomycin δ2. The combined genetic information was utilized to identify an abm-related locus (named ctj) from the draft genome of Streptomyces sp. C. Cross-complementation experiments and in vitro studies with CtjF, the AbmI homolog, suggest the production of a similar 4′-thiofuranosyl cytosine in this organism. In total, the genetic and biochemical data provide a biosynthetic template for assembling siderophore-inhibitor conjugates, and modifying the albomycin scaffold to generate new derivatives.

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Section: Resultsmentioning

confidence: 99%

Biosynthesis of Albomycin δ₂ Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates

et al. 2012

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Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens

Lin

Zhao

et al. 2018

Nat Commun

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Development of effective antimicrobial agents continues to be a great challenge, particularly due to the increasing resistance of superbugs and frequent hospital breakouts. There is an urgent need for more potent and safer antibiotics with novel scaffolds. As historically many commercial drugs were derived from natural products, discovery of antimicrobial agents from complex natural product structures still holds a great promise. Herein, we report the total synthesis of natural albomycins δ1 (1a), δ2 (1b), and ε (1c), which validates the structures of these peptidylnucleoside compounds and allows for synthetic access to bioactive albomycin analogs. The efficient synthesis of albomycins enables extensive evaluations of these natural products against model bacteria and clinical pathogens. Albomycin δ2 has the potential to be developed into an antibacterial drug to treat Streptococcus pneumoniae and Staphylococcus aureus infections.

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ChemInform Abstract: CONSTITUTION OF THE DEFERRIFORM OF ALBOMYCINS Δ1, Δ2, AND ε

Abstract: The complete manuscript of this communication appears in: Angew. Chem. Suppl. 1982, 1322. DOI:

Cited by 2 publications

References 1 publication

Biosynthesis of Albomycin δ₂ Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates

Biosynthesis of Albomycin δ₂ Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates

Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens

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ChemInform Abstract: CONSTITUTION OF THE DEFERRIFORM OF ALBOMYCINS Δ1, Δ2, AND ε

Abstract: The complete manuscript of this communication appears in: Angew. Chem. Suppl. 1982, 1322. DOI:

Cited by 2 publications

References 1 publication

Biosynthesis of Albomycin δ2 Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates

Biosynthesis of Albomycin δ2 Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates

Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens

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Biosynthesis of Albomycin δ₂ Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates

Biosynthesis of Albomycin δ₂ Provides a Template for Assembling Siderophore and Aminoacyl-tRNA Synthetase Inhibitor Conjugates