期刊
ACS CENTRAL SCIENCE
卷 2, 期 2, 页码 99-108出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.5b00331
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资金
- NCI NIH HHS [P30 CA060553] Funding Source: Medline
- NCRR NIH HHS [S10 RR019071] Funding Source: Medline
- NIGMS NIH HHS [F32 GM100658, R01 GM067725, T32 GM105538, P01 GM077596] Funding Source: Medline
- NIH HHS [S10 OD012016] Funding Source: Medline
For more than half a century the pharmaceutical industry has sifted through natural products produced by microbes, uncovering new scaffolds and fashioning them into a broad range of vital drugs. We sought a strategy to reinvigorate the discovery of natural products with distinctive structures using bacterial genome sequencing combined with metabolomics. By correlating genetic content from 178 actinomycete genomes with mass spectrometry-enabled analyses of their exported metabolomes, we paired new secondary metabolites with their biosynthetic gene clusters. We report the use of this new approach to isolate and characterize tambromycin, a new chlorinated natural product, composed of several nonstandard amino acid monomeric units, including a unique pyrrolidine-containing amino acid we name tambroline. Tambromycin shows antiproliferative activity against cancerous human B-and T-cell lines. The discovery of tambromycin via large-scale correlation of gene clusters with metabolites (a.k.a. metabologenomics) illuminates a path for structure-based discovery of natural products at a sharply increased rate.
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