Verzweigte und kettenverlängerte Zucker, XXXI. Synthese des Sauerstoffanalogons der Desferriform von δ<sub>1</sub>‐Albomycin

Paulsen, Hans; Brieden, M.; Benz, G.

doi:10.1002/jlac.198719870702

Cited by 37 publications

(16 citation statements)

References 29 publications

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“…Elucidation of the thioether group formation in albomycin is very important because substitution of the sulfur for an oxygen resulted in complete loss of the bioactivity of albomycins. 4 …”

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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“…Elucidation of the thioether group formation in albomycin is very important because substitution of the sulfur for an oxygen resulted in complete loss of the bioactivity of albomycins. 4 …”

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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“…The presence of sulfur in 38 is essential for the observed antimicrobial activity, because the oxygen ring analogue of albomycin is totally inactive. 53 …”

Section: Thiosugarsmentioning

confidence: 99%

The biosynthesis of nitrogen-, sulfur-, and high-carbon chain-containing sugars

2013

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Carbohydrates serve many structural and functional roles in biology. While the majority of monosaccharides are characterized by the chemical composition: (CH2O)n, modifications including deoxygenation, C-alkylation, amination, O- and N-methylation, which are characteristic of many sugar appendages of secondary metabolites, are not uncommon. Interestingly, some sugar molecules are formed via modifications including amine oxidation, sulfur incorporation, and “high-carbon” chain attachment. Most of these unusual sugars have been identified over the past several decades as components of microbially produced natural products, although a few high-carbon sugars are also found in the lipooligosaccharides of the outer cell walls of Gram-negative bacteria. Despite their broad distribution in nature, these sugars are considered “rare” due to their relative scarcity. The biosynthetic steps that underlie their formation continue to perplex researchers to this day and many questions regarding key transformations remain unanswered. This review will focus on our current understanding of the biosynthesis of unusual sugars bearing oxidized amine substituents, thio-functional groups, and high-carbon chains.

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“…However, no total synthesis of albomycins has been reported. In one study 22 , an oxygen analog of 1a was synthesized. Surprisingly, a single replacement of the sulfur with oxygen resulted in the complete loss of antibacterial activity, suggesting a critical role of the sulfur atom in the activity of albomycins.…”

Section: Introductionmentioning

confidence: 99%

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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Verzweigte und kettenverlängerte Zucker, XXXI. Synthese des Sauerstoffanalogons der Desferriform von δ₁‐Albomycin

Cited by 37 publications

References 29 publications

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

The biosynthesis of nitrogen-, sulfur-, and high-carbon chain-containing sugars

Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens

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Verzweigte und kettenverlängerte Zucker, XXXI. Synthese des Sauerstoffanalogons der Desferriform von δ1‐Albomycin

Cited by 37 publications

References 29 publications

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

The biosynthesis of nitrogen-, sulfur-, and high-carbon chain-containing sugars

Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens

Contact Info

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Verzweigte und kettenverlängerte Zucker, XXXI. Synthese des Sauerstoffanalogons der Desferriform von δ₁‐Albomycin

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