Metabologenomics: Correlation of microbial gene clusters with metabolites drives discovery of a nonribosomal peptide with an unusual amino acid monomer

Anthony W. Goering; Ryan A. McClure; James R. Doroghazi; Jessica C. Albright; Nicole A. Haverland; Yongbo Zhang; Kou San Ju; Regan J. Thomson; William W. Metcalf; Neil L. Kelleher

doi:10.1021/acscentsci.5b00331

Metabologenomics: Correlation of microbial gene clusters with metabolites drives discovery of a nonribosomal peptide with an unusual amino acid monomer

Anthony W. Goering, Ryan A. McClure, James R. Doroghazi, Jessica C. Albright, Nicole A. Haverland, Yongbo Zhang, Kou San Ju, Regan J. Thomson, William W. Metcalf^*, Neil L. Kelleher

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	99-108
Number of pages	10
Journal	ACS Central Science
Volume	2
Issue number	2
DOIs	https://doi.org/10.1021/acscentsci.5b00331
State	Published - Feb 24 2016

Funding

We thank the staff at Northwestern University's Integrated Molecular Structure Education and Research Center (IMSERC), especially Dr. Derek Nelson, Dr. Andrew Ott, and Dr. Yuyang Wu. We also thank the Agricultural Research Service of the United States Department of Agriculture for providing the bacterial strains used in this publication. NMR spectroscopy experiments were supported by the National Institute of Health (NIH) Award NIH 1S10OD012016-01/1S10RR019071-01A1. This work was also supported by the Departments of Chemistry and Molecular Biosciences at Northwestern University and Grants GM067725 (to N.L.K.) and GM077596 (to W.W.M.) from the NIH. J.R.D. was supported by the Institute for Genomic Biology IGB Fellows Program at UIUC and K.S.J. by NIH Ruth L. Kirchstein National Service Research Award F32GM100658. Additional funding was provided by an Institute for Genomic Biology Proof of Concept grant.

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acscentsci.5b00331

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Goering, A. W., McClure, R. A., Doroghazi, J. R., Albright, J. C., Haverland, N. A., Zhang, Y., Ju, K. S., Thomson, R. J., Metcalf, W. W., & Kelleher, N. L. (2016). Metabologenomics: Correlation of microbial gene clusters with metabolites drives discovery of a nonribosomal peptide with an unusual amino acid monomer. ACS Central Science, 2(2), 99-108. https://doi.org/10.1021/acscentsci.5b00331

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abstract = "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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Goering, AW, McClure, RA, Doroghazi, JR, Albright, JC, Haverland, NA, Zhang, Y, Ju, KS, Thomson, RJ, Metcalf, WW & Kelleher, NL 2016, 'Metabologenomics: Correlation of microbial gene clusters with metabolites drives discovery of a nonribosomal peptide with an unusual amino acid monomer', ACS Central Science, vol. 2, no. 2, pp. 99-108. https://doi.org/10.1021/acscentsci.5b00331

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AU - Kelleher, Neil L.

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Metabologenomics: Correlation of microbial gene clusters with metabolites drives discovery of a nonribosomal peptide with an unusual amino acid monomer

Abstract

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