Angucycline group antibiotics.

A systematic analysis of all naturally-occurring glycosylated bacterial secondary metabolites reported in the scientific literature up through early 2013 is presented. This comprehensive analysis of 15 940 bacterial natural products revealed 3426 glycosides containing 344 distinct appended carbohydrates and highlights a range of unique opportunities for future biosynthetic study and glycodiversification efforts.

/pdf/a-comprehensive-review-of-glycosylated-bacterial-natural-4txxvyk4h3.pdf

A comprehensive review of glycosylated bacterial natural products.

About 30% of the worldwide sales of drugs are based on natural products. Though recombinant proteins and peptides account for increasing sales rates, the superiority of low-molecular mass compounds in human diseases therapy remains undisputed mainly due to more favorable compliance and bioavailability properties. In the past, new therapeutic approaches often derived from natural products. Numerous examples from medicine impressively demonstrate the innovative potential of natural compounds and their impact on progress in drug discovery and development. However, natural products are currently undergoing a phase of reduced attention in drug discovery because of the enormous effort which is necessary to isolate the active principles and to elucidate their structures. To meet the demand of several hundred thousands of test samples that have to be submitted to high-throughput screening (HTS) new strategies in natural product chemistry are necessary in order to compete successfully with combinatorial chemistry. Today, pharmaceutical companies have to spend approximately US $350 million to develop a new drug. Currently, approaches to improve and accelerate the joint drug discovery and development process are expected to arise mainly from innovation in drug target elucidation and lead finding. Breakthroughs in molecular biology, cell biology, and genetic engineering in the 1980 s gave access to understanding diseases on the molecular or on the gene level. Subsequently, constructing novel target directed screening assay systems of promising therapeutic significance, automation, and miniaturization resulted in HTS approaches changing the industrial drug discovery process drastically. Furthermore, elucidation of the human genome will provide access to a dramatically increased number of new potential drug targets that have to be evaluated for drug discovery. HTS enables the testing of an increasing number of samples. Therefore, new concepts to generate large compound collections with improved structural diversity are desirable.

Bioactive Agents from Natural Sources: Trends in Discovery and Application

INTRODUCTION The human microbiome has been correlated with several health and disease conditions, but the molecular mechanisms underlying these correlations remain largely unexplored. Biologically active small molecules that are produced by the human microbiome offer an important route for exploring these mechanisms because they often mediate important microbe-microbe and microbe-host interactions. In bacterial genomes, small-molecule biosynthetic genes are usually encoded in distinct clusters known as biosynthetic gene clusters (BGCs), which enables scientists to use computational tools for recognizing them and predicting their products. Here, we present a hybrid strategy that uses computational and synthetic biology tools for discovering microbiome-encoded small molecules. RATIONALE Previous efforts to discover small-molecule BGCs from the human microbiome relied mainly on analyzing genomic data of sequenced bacterial isolates. Although this approach has revealed the enormous and largely untapped diversity of microbiome-encoded BGCs, it fails to report on the biosynthetic potential of members of the human microbiome that have not yet been cultured or isolated: the majority of species in metagenomic sequencing data. Therefore, we sought to develop a computational algorithm that discovers small-molecule BGCs directly in complex metagenomic sequencing data of the human microbiome: metagenomic identifier of biosynthetic gene clusters (MetaBGC). First, high-performance probabilistic models for identifying homologs of a biosynthetic enzyme of interest are built specifically for use with complex metagenomic datasets(MetaBGC-Build). Next, these models are used to identify biosynthetic genes in thousands of metagenomic datasets of the human microbiome at the single-read level (MetaBGC-Identify). Finally, identified biosynthetic reads are quantified in the entire cohort of samples (MetaBGC-Quantify) and clustered into biosynthetic read bins on the basis of their abundance profiles across samples (MetaBGC-Cluster). To evaluate the utility of this approach, we used it to discover BGCs for type II polyketides, a clinically relevant class of small molecules, directly from metagenomic sequencing data of the human microbiome. RESULTS We applied MetaBGC to 3203 metagenomic samples of the human microbiome originating from Western (subjects from the United States, Spain, and Denmark) and non-Western (subjects from China and Fiji) populations and from every major human body site (gut, mouth, skin, and vagina). Overall, we discovered 13 complete BGCs that potentially encode type II polyketides; eight of these were encoded by diverse bacterial isolates of the human microbiome in a strain-specific manner and five could not be assigned to any sequenced species. Type II polyketide BGCs are found in three major human body sites, gut, mouth, and skin, and at least six of them are transcribed under host-colonization conditions and widely distributed in different human populations (e.g., 46% of healthy subjects from the United States encode at least one BGC in their gut, oral, or skin microbiome). Next, we selected two of the identified BGCs for experimental characterization, one from the oral microbiome and another from the gut microbiome. We used a synthetic biology strategy in which metagenomically discovered BGCs are genetically engineered and expressed in various heterologous hosts without the need for cultivation of the native producer. Using this strategy, we successfully purified and solved the structures of five new type II polyketide molecules as the products of the two characterized BGCs. Finally, we show that two of the discovered molecules exert strong antibacterial activities against members of the human microbiome that occupy the same niche as their producer, implying a possible role in microbe-microbe competition. CONCLUSION We developed a hybrid strategy that combines computational and experimental techniques for discovering and characterizing small-molecule BGCs directly from complex datasets of the human microbiome. Using this strategy, we discovered that a clinically relevant class of molecules, type II polyketides, are widely encoded in the human microbiome and that human microbiome–derived polyketides resemble in structure and biological activity clinically used ones. Our approach is generally applicable to other classes of small molecules and can be used to systematically unveil the chemical potential of the human microbiome—a goal that is useful for both mechanistic microbiome explorations and drug discovery.

A metagenomic strategy for harnessing the chemical repertoire of the human microbiome

The colored urdamycins A to F, six new angucycline antibiotics produced by Streptomyces fradiae strain Tu 2717, were detected by chemical screening. They are biologically active against Gram-positive bacteria and stem cells of murine L1210 leukemia. The urdamycins are glycosides and differ in their aglycones, which can be liberated by acidic hydrolysis besides the sugars D-olivose and L-rhodinose. The structure of the main compound, urdamycin A, follows from the spectroscopic and chemical data in connection with an X-ray analysis. The aglycone urdamycinone A is identical with aquayamycin. The structures of urdamycin B, E, F and partial structures of urdamycin C and D, will be presented in a subsequent paper. The new term "angucycline/angucyclinone" is used for an increasing group of related antibiotics.

https://www.jstage.jst.go.jp/article/antibiotics1968/39/12/39_12_1657/_pdf

Metabolic products of microorganisms. 234 urdamycins, new angucycline antibiotics from streptomyces fradiae

Elloramycin (1), a new antibiotic produced by Streptomyces olivaceus strain Tu 2353, was detected by chemical screening. The dark yellow compound, molecular formula C32H36O15, is weakly active against a variety of Gram-positive bacteria, especially streptomycetes and against stem cells of L-1210 leukemia. Acidic hydrolysis of the antibiotic liberated elloramycinone (3) as aglycone and 2,3,4-tri-O-methyl-L-rhamnose, which was identified as methyl glycoside 5b. The structure of elloramycin was established by comparison of the spectra (UV, 1H NMR, 13C NMR) with those of the known tetracenomycin C (2), 3 and the fact that 2 and 3 gave the same tetramethyl ether after permethylation. Elloramycin is an anthracycline-like antibiotic, the aglycone resembles tetracenomycin C, the sugar is connected in a phenolic alpha-glycosidic linkage.

Metabolic products of microorganisms. 225. Elloramycin, a new anthracycline-like antibiotic from Streptomyces olivaceus. Isolation, characterization, structure and biological properties.

Tetracenomycins B3 and D3, besides tetracenomycin D (D1), were produced by a blocked mutant of the elloramycin producer Streptomyces olivaceus TU 2353. The compounds were isolated as red powders, and their structures were elucidated by comparing their physicochemical data with those of the known tetracenomycins A2, B1, B2, D and E. Tetracenomycin B3 (2), the main compound, and tetracenomycin D (3) were antibiotically inactive against Gram-positive and Gram-negative bacteria, whereas tetracenomycin D3 (1) showed a moderate activity against Bacillus subtilis and Arthrobacter aurescens. Tetracenomycin B3 (2) is the key intermediate where the biosynthesis of the elloramycins branches off from the line leading to tetracenomycin C (5) as the final product of the tetracenomycin biosynthesis branch.

Metabolic products of microorganisms. 249. Tetracenomycins B3 and D3, key intermediates of the elloramycin and tetracenomycin C biosynthesis.

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Metabolic products of microorganisms. 225. Elloramycin, a new anthracycline-like antibiotic from Streptomyces olivaceus. Isolation, characterization, structure and biological properties.

Metabolic products of microorganisms. 249. Tetracenomycins B3 and D3, key intermediates of the elloramycin and tetracenomycin C biosynthesis.