The production, isolation, and characterization of a grisein‐like sideromycin complex

Maehr, Hubert; Berger, Jacob

doi:10.1002/bit.260110608

Cited by 10 publications

(3 citation statements)

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“…Albomycins are broad-spectrum antibiotics that have been isolated several times from soil-dwelling actinomycetes in various drug discovery programs since the first report dating back 60 years . Their extreme antibacterial potency and extended spectrum has prompted numerous attempts to develop albomycins into a commercial drug − and likewise spawned a longstanding interest in elucidating the mechanism of action of albomycins . These studies have revealed that albomycins are Trojan horse antibiotics that consist of a ferrichrome-type siderophore component that is indiscriminately taken up by bacteria as a mechanism to scavenge iron from the environment.…”

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“…ATCC 700974, the cytosine base carries two modifications: one is methylation of the N3 and the other is carbamoylation of the N4 imino nitrogen. These modifications are known to significantly enhance the bioactivity of albomycins since two minor congeners that either lack the carbamoyl group (albomycin ε) or with the N 3 -methylcytosine substituted by a N 3 -methyluracil (albomycin δ 1 ) have been isolated and assessed . While the C-terminal nonproteinogenic amino acid contains several uncommon features such as a thioether modification of the furanoside and N4-carbamoylation of cytosine, N3-methylated cytosine is found only in eukaryotic tRNAs and rRNAs and is thought to finely modulate structures and functions of the RNAs.…”

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

et al. 2012

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“…In summary, ABM is an antibacterial agent that was chosen for pharmaceutical development long before the genomic era (6,12,13,44). A rational metabolic engineering strategy for increasing ABM production was adopted in this study.…”

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A Branch Point of Streptomyces Sulfur Amino Acid Metabolism Controls the Production of Albomycin

Kulkarni

Zeng

Zhou

et al. 2016

Appl Environ Microbiol

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c Albomycin (ABM), also known as grisein, is a sulfur-containing metabolite produced by Streptomyces griseus ATCC 700974. Genes predicted to be involved in the biosynthesis of ABM and ABM-like molecules are found in the genomes of other actinomycetes. ABM has potent antibacterial activity, and as a result, many attempts have been made to develop ABM into a drug since the last century. Although the productivity of S. griseus can be increased with random mutagenesis methods, understanding of Streptomyces sulfur amino acid (SAA) metabolism, which supplies a precursor for ABM biosynthesis, could lead to improved and stable production. We previously characterized the gene cluster (abm) in the genome-sequenced S. griseus strain and proposed that the sulfur atom of ABM is derived from either cysteine (Cys) or homocysteine (Hcy). The gene product, AbmD, appears to be an important link between primary and secondary sulfur metabolic pathways. Here, we show that propargylglycine or iron supplementation in growth media increased ABM production by significantly changing the relative concentrations of intracellular Cys and Hcy. An SAA metabolic network of S. griseus was constructed. Pathways toward increasing Hcy were shown to positively impact ABM production. The abmD gene and five genes that increased the Hcy/Cys ratio were assembled downstream of hrdBp promoter sequences and integrated into the chromosome for overexpression. The ABM titer of one engineered strain, SCAK3, in a chemically defined medium was consistently improved to levels ϳ400% of the wild type. Finally, we analyzed the production and growth of SCAK3 in shake flasks for further process development. The Streptomyces genus was established at the beginning of the golden age of antibiotic discovery (1). Streptomyces griseus, a representative organism of the genus (2), was shown during this time to produce streptomycin (3), which has been clinically used to treat bacterial infections and other human diseases. It is well known that Streptomyces organisms in general have a large biosynthetic potential, being capable of producing many bioactive secondary metabolites-the S. griseus strains producing albomycin (ABM) are no exception. ABM was named by former Soviet Union scientists and underwent clinical investigations well before the information was released to the English-speaking scientific world (4). The biological activity and chemical constitution of ABM were later reported to be nearly identical to those of grisein, which was isolated from a distinct subtype of S. griseus by U.S. scientists in the 1940s (5-7). Despite its remarkable properties, continued studies of ABM were not pursued, partly because of the poor yields (8) and unpublicized research on the microorganism (9, 10). At present, the wealth of Streptomyces genomic information that is publically available provides the possibility of using a systems biology approach to uncover new aspects of Streptomyces metabolism and potentially overcome the production bottleneck.ABM and ABM-like secondary metabolites...

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Konstitution der Desferriform der Albomycine ?1, ?2, ?

Benz

Schr�der

Kurz

et al. 1982

Angew. Chem. Int. Ed. Engl.

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The production, isolation, and characterization of a grisein‐like sideromycin complex

Cited by 10 publications

References 14 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

A Branch Point of Streptomyces Sulfur Amino Acid Metabolism Controls the Production of Albomycin

Konstitution der Desferriform der Albomycine ?1, ?2, ?

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The production, isolation, and characterization of a grisein‐like sideromycin complex

Cited by 10 publications

References 14 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

A Branch Point of Streptomyces Sulfur Amino Acid Metabolism Controls the Production of Albomycin

Konstitution der Desferriform der Albomycine ?1, ?2, ?

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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