Arixanthomycins A–C: Phylogeny-Guided Discovery of Biologically Active eDNA-Derived Pentangular Polyphenols

Kang, Hahk‐Soo; Brady, Sean F.

doi:10.1021/cb500141b

Cited by 59 publications

(59 citation statements)

References 27 publications

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“…We have shown eSNaPD classification to be a robust indicator of a functional relationship between a microbiome-derived gene cluster yielding an AD or KS domain sequence tag and a curated known gene cluster (20)(21)(22). Based on empirical data from previous metagenomic analyses (20)(21)(22)(23), the homology cutoffs used in this study (e value < 10 −100 ) will identify gene clusters with a high likelihood of encoding either the same metabolite or a novel derivative (congener) of the metabolite encoded by the matching curated gene cluster.…”

Section: Resultsmentioning

confidence: 99%

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Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity

Charlop–Powers

Pregitzer

Lemetre

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Numerous therapeutically relevant small molecules have been identified from the screening of natural products (NPs) produced by environmental bacteria. These discovery efforts have principally focused on culturing bacteria from natural environments rich in biodiversity. We sought to assess the biosynthetic capacity of urban soil environments using a phylogenetic analysis of conserved NP biosynthetic genes amplified directly from DNA isolated from New York City park soils. By sequencing genes involved in the biosynthesis of nonribosomal peptides and polyketides, we found that urban park soil microbiomes are both rich in biosynthetic diversity and distinct from nonurban samples in their biosynthetic gene composition. A comparison of sequences derived from New York City parks to genes involved in the biosynthesis of biomedically important NPs produced by bacteria originally collected from natural environments around the world suggests that bacteria producing these same families of clinically important antibiotics, antifungals, and anticancer agents are actually present in the soils of New York City. The identification of new bacterial NPs often centers on the systematic exploration of bacteria present in natural environments. Here, we find that the soil microbiomes found in large cities likely hold similar promise as rich unexplored sources of clinically relevant NPs.

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Section: Resultsmentioning

confidence: 99%

“…AD and KS amplicons were assigned to known biosynthetic gene clusters using the eSNaPD program (18,19). Empirical exploration with the eSNaPD algorithm has shown that e values as high as 10 −40 to −60 return reliable gene cluster predictions (20)(21)(22). We used an expectation value to 10 −100 for this analysis.…”

Section: Methodsmentioning

confidence: 99%

Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity

Charlop–Powers

Pregitzer

Lemetre

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…The first heterologous expression of a natural product cluster using TAR was reported later that year, with the capture and expression of a number of fluostatins from environmental DNA (eDNA) clusters in a Streptomyces albus host [45]. The polyketides arixanthomycin A-C were also discovered using this strategy, yielding compounds with cytotoxicity in the sub-micromolar range [46]. …”

Section: Methodologiesmentioning

confidence: 99%

“…A cosmid/BAC library can be generated to capture an entire genome or metagenome, and direct capture can be then used to assemble the desired cluster in a single vector, as demonstrated by the capture of numerous clusters from eDNA libraries, as noted earlier [43, 45–46, 51, 61]. …”

Section: Comparison Of Direct Capture With Traditional Natural Promentioning

confidence: 99%

Direct Capture Technologies for Genomics-Guided Discovery of Natural Products

Chan¹,

Maria²,

2016

CTMC

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Microbes are important producers of natural products, which have played key roles in understanding biology and treating disease. However, the full potential of microbes to produce natural products has yet to be realized; the overwhelming majority of natural product gene clusters encoded in microbial genomes remain “cryptic”, and have not been expressed or characterized. In contrast to the fast-growing number of genomic sequences and bioinformatic tools, methods to connect these genes to natural product molecules are still limited, creating a bottleneck in genome-mining efforts to discover novel natural products. Here we review developing technologies that leverage the power of homologous recombination to directly capture natural product gene clusters and express them in model hosts for isolation and structural characterization. Although direct capture is still in its early stages of development, it has been successfully utilized in several different classes of natural products. These early successes will be reviewed, and the methods will be compared and contrasted with existing traditional technologies. Lastly, we will discuss the opportunities for the development of direct capture in other organisms, and possibilities to integrate direct capture with emerging genome-editing techniques to accelerate future study of natural products.

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“…The method is continuously further advanced to streamline the process and to enable the application of further host organisms, e.g., Bacillus subtilis . TAR cloning for example enabled the heterologous expression of BGCs in S. coelicolor yielding the lipopeptide taromycin A and in S. albus yielding arixanthomycins A–C .…”

Section: Genome Miningmentioning

confidence: 99%

Toolbox for Antibiotics Discovery from Microorganisms

Fisch

Schäberle

2016

Archiv der Pharmazie

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Microorganisms produce a vast array of biologically active metabolites. Such compounds are applied by humans to positively influence their health and, therefore, natural products serve as drug leads for pharmaceutical and medicinal chemistry. In this minireview, tools for the discovery and the production of potential drug leads are explained. A snapshot is provided, starting from the isolation of new producer strains, across genomic mining of (meta)genomes to identify biosynthetic gene clusters corresponding to natural products, toward heterologous expression to produce potential drug leads.

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Arixanthomycins A–C: Phylogeny-Guided Discovery of Biologically Active eDNA-Derived Pentangular Polyphenols

Cited by 59 publications

References 27 publications

Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity

Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity

Direct Capture Technologies for Genomics-Guided Discovery of Natural Products

Toolbox for Antibiotics Discovery from Microorganisms

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