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Research Article

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

Kou-San Ju, Jiangtao Gao, James R. Doroghazi, Kwo-Kwang A. Wang, Christopher J. Thibodeaux, Steven Li, Emily Metzger, John Fudala, Joleen Su, Jun Kai Zhang, Jaeheon Lee, Joel P. Cioni, Bradley S. Evans, Ryuichi Hirota, David P. Labeda, Wilfred A. van der Donk, and William W. Metcalf
PNAS first published August 31, 2015; https://doi.org/10.1073/pnas.1500873112
Kou-San Ju
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Jiangtao Gao
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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James R. Doroghazi
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Kwo-Kwang A. Wang
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Christopher J. Thibodeaux
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Steven Li
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Emily Metzger
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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John Fudala
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Joleen Su
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Jun Kai Zhang
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
bDepartment of Microbiology, University of Illinois, Urbana, IL 61801;
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Jaeheon Lee
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Joel P. Cioni
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
bDepartment of Microbiology, University of Illinois, Urbana, IL 61801;
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Bradley S. Evans
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
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Ryuichi Hirota
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
cDepartment of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8530, Japan;
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David P. Labeda
dBacterial Foodborne Pathogens and Mycology Research, US Department of Agriculture, Agricultural Research Service, National Center for Agricultural Utilization Research, Peoria, IL 61604;
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Wilfred A. van der Donk
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
eDepartment of Chemistry and Howard Hughes Medical Institute, University of Illinois, Urbana, IL 61081
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  • For correspondence: vddonk@illinois.edu metcalf@illinois.edu
William W. Metcalf
aCarl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801;
bDepartment of Microbiology, University of Illinois, Urbana, IL 61801;
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  • For correspondence: vddonk@illinois.edu metcalf@illinois.edu
  1. Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved July 31, 2015 (received for review January 14, 2015)

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Significance

The discovery of natural products, an important source of human medicines, is critical for the development of new therapeutics against health threats, including cancer and multidrug-resistant pathogens. Yet, in recent years, industrial development of pharmaceuticals from natural products has been stymied due to a variety of reasons, including the repeated discovery of previously known compounds. Here, we demonstrate large-scale genomics as one potential solution to this problem by mining a collection of 10,000 actinomycetes for novel phosphonic acids, an important class of natural products with antimicrobial, antiviral, antimalarial, and herbicidal activities. The framework described here provides a foundation for rapid, large-scale discovery of other classes of natural products and their use as lead compounds in the pharmaceutical industry.

Abstract

Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed “genome mining” as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N5-hydroxyarginine; valinophos, an N-acetyl l-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products.

  • natural products
  • genome mining
  • phosphonic acid
  • antibiotic

Footnotes

  • ↵1To whom correspondence may be addressed. Email: vddonk{at}illinois.edu or metcalf{at}illinois.edu.
  • Author contributions: K.-S.J., J.G., J.R.D., W.A.v.d.D., and W.W.M. designed research; K.-S.J., J.G., J.R.D., K.-K.A.W., C.J.T., S.L., E.M., J.F., J.S., J.K.Z., J.L., J.P.C., B.S.E., and R.H. performed research; K.-S.J., J.G., J.R.D., K.-K.A.W., C.J.T., J.L., B.S.E., D.P.L., W.A.v.d.D., and W.W.M. analyzed data; and K.-S.J., J.G., W.A.v.d.D., and W.W.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The sequences reported in this paper have been deposited in the BioProject database, ncbi.nlm.nih.gov/bioproject (accession no. PRJNA238534).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1500873112/-/DCSupplemental.

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Discovery of phosphonates by genome mining
Kou-San Ju, Jiangtao Gao, James R. Doroghazi, Kwo-Kwang A. Wang, Christopher J. Thibodeaux, Steven Li, Emily Metzger, John Fudala, Joleen Su, Jun Kai Zhang, Jaeheon Lee, Joel P. Cioni, Bradley S. Evans, Ryuichi Hirota, David P. Labeda, Wilfred A. van der Donk, William W. Metcalf
Proceedings of the National Academy of Sciences Aug 2015, 201500873; DOI: 10.1073/pnas.1500873112

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Discovery of phosphonates by genome mining
Kou-San Ju, Jiangtao Gao, James R. Doroghazi, Kwo-Kwang A. Wang, Christopher J. Thibodeaux, Steven Li, Emily Metzger, John Fudala, Joleen Su, Jun Kai Zhang, Jaeheon Lee, Joel P. Cioni, Bradley S. Evans, Ryuichi Hirota, David P. Labeda, Wilfred A. van der Donk, William W. Metcalf
Proceedings of the National Academy of Sciences Aug 2015, 201500873; DOI: 10.1073/pnas.1500873112
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