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ARS Home » Midwest Area » Peoria, Illinois » National Center for Agricultural Utilization Research » Mycotoxin Prevention and Applied Microbiology Research » Research » Publications at this Location » Publication #306331
Title: Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

Author
item JU, KOU-SAN - University Of Illinois
item GAO, JIANGTAO - University Of Illinois
item DOROGHAZI, JAMES - University Of Illinois
item LI, STEVEN - University Of Illinois
item METZGER, EMILY - University Of Illinois
item FUDALA, JOHN - University Of Illinois
item SU, JOLEEN - University Of Illinois
item ZHANG, JUNKAI - University Of Illinois
item CIONI, JOEL - University Of Illinois
item LEE, JAEHEON - University Of Illinois
item EVANS, BRADLEY - University Of Illinois
item HIROTA, RYUICHI - University Of Illinois
item Labeda, David
item VAN DER DONK, WILFRED - University Of Illinois
item METCALF, WILLIAM - University Of Illinois

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/31/2015
Publication Date: 9/29/2015
Publication URL: https://handle.nal.usda.gov/10113/62324
Citation: Ju, K.-S., Gao, J., Doroghazi, J.R., Wang, K.-K.A., Thibodeaux, C.J., Li, S., Metzger, E., Fudala, J., Su, J., Zhang, J.K., Lee, J., Cioni, J.P., Evans, B.S., Hirota, R., Labeda, D.P., van der Donk, W.A., Metcalf, W.W. 2015. Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes. Proceedings of the National Academy of Sciences. 112(39):12175-12180.

Interpretive Summary: Although the number of infectious bacteria resistant to antibiotics currently available is increasing, the search for new and effective antibiotics has become exceedingly difficult over the past three decades. A novel genomic screening approach targeting the ability of microoganisms to produce compounds called phosphonic acids was used to evaluate a large and diverse collection of actinobacterial strains held in the ARS Culture Collection. This study demonstrated the utility of the screening method through the discovery of 287 positive strains and 12 novel phosphonate-containing natural products. These novel natural products and those potentially produced by the positive strains will be extremely valuable to the pharmaceutical and biotechnology industries as either new medicinally or agriculturally significant agents in their own right, or as compounds with novel structure to be subsequently chemically modified to produce new and enhanced bioactivity. Moreover, this study also confirms the value of maintaining large archival collections of diverse microorganisms and demonstrates that natural product screening programs over the past 60 years have not discovered all of the novel antibiotics that actinobacteria are capable of producing.

Technical Abstract: Although natural products have been a particularly rich source of human medicines, the rate at which new molecules are being discovered is declining precipitously. Based on the large number of natural product biosynthetic genes in microbial genomes, many have suggested “genome mining” as an approach to revitalize discovery efforts; however this idea has yet to be demonstrated on a large-scale. To test the feasibility of high-throughput genome mining, we screened a collection of over 10,000 Actinobacteria for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Initial characterization of the 287 positive strains allowed identification of 12 previously undescribed natural products, including an unusual thiohydroximate phosphonate and a broad-spectrum phosphonopeptide antibiotic. Analysis of the genome sequences from the remaining strains suggests that numerous additional phosphonate natural products await discovery.