Bringing genomics into natural products discovery

NIGMS to fund research that will use genomic and metagenomic sequencing data to find natural products

Jeffrey Bouley
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BETHESDA, Md.—Last year, the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) was looking to award $6.8 million to fund projects that would create platforms designed to take genomic and metagenomic sequencing data and use that data to discover natural products that could be useful as therapeutics. Apparently, there were no viable takers then, and that request for applications, previously called RFA-GM-14-002, has been reissued as RFA-GM-15-001 this year.
The amount to fund what are hoped to be two projects has gone down some—likely due to recent budget cuts across the federal government—to a total of $4.5 million, but the need remains high, according to NIGMS.
“Natural products are a prolific source of therapeutic drugs because they have been selected through evolution to be biologically active. New opportunities for natural products development made possible by genomic discoveries are poised to rapidly expand the utility of this critically important resource,” wrote Dr. Barbara Gerratana, a program director in the Division of Pharmacology, Physiology, and Biological Chemistry at NIGMS, in March on the NIGMS Feedback Loop Blog. To further stimulate studies in this area, she notes, NIGMS has issued the final funding opportunity announcement for Genomes to Natural Products research, with applications due by June 10.
“We’re looking for multidisciplinary teams of experts in natural products, synthetic biology, bioinformatics, genomics and analytical chemistry to develop high-throughput natural products discovery platforms based on a synthetic biology approach that leverages genomics and metagenomics data,” Gerratana added. “The goal is to deliver broadly applicable, context-independent (i.e., independent of organism and/or natural products class) and game-changing tools, methods and resources in natural products discovery. The funded research also should lead to a deeper understanding of the regulation of natural products biosynthesis.”
More detailed information can be found on the opportunity at In addition, Gerratana went so far as to invite interested parties not only to talk with potential collaborators but to discuss their applications with her personally via her NIH email address.
NIGMS states in the overview of the RFA-GM-15-001 funding opportunity announcement (FOA) that, having been optimized through evolutionary genetic processes for their biological activity, natural products serve as defensive and signaling molecules, and impart defining chemical features that help make organisms biologically distinct—moreover, some 75 percent of antibacterial and anticancer drugs are natural products or are inspired by natural products.
“Despite their impact, the discovery process for natural products has conceptually and technically not changed over the past three decades. This ‘grind and find’ method entails identification of natural products through biological or phenotypic screening of partially purified mixtures of compounds obtained from cultivable organisms,” NIGMS notes. “Thus, this method is limited to organisms that can be cultured and whose biosynthetic operons are sufficiently expressed under culture conditions to provide assayable amounts of active material. These intrinsic limitations have led to a significant reduction in the rate of new discoveries. Recent studies of known natural products' producers suggest that less than 1 percent of bacteria and fungi can be cultivated and of these, only a small fraction of their natural product operons are active under culture conditions. This suggests that the current approach to discovery of natural products has barely tapped into the potential pool of encoded products.”
Research proposed should be applicable regardless of whether the natural product source is cultivable, or the biosynthetic pathways are expressed in the native producer; be applicable to a large variety of organisms and/or biosynthetic operons and with the production of natural products in model organisms being sufficient for high-throughput chemical characterization; include uncharacterized natural products producers and/or biosynthetic operons and should not necessarily focus on natural products of proven medical relevance; and advance studies of the regulation and function of biosynthetic enzymes, with the expectation that it will contribute to the identification of novel enzymatic function and chemical entities.
“The last decade has witnessed rapid technical advances and cost-reduction in DNA sequencing, DNA synthesis, and DNA cloning, enabling the sequencing of a wealth of genomes and metagenomic DNA,” NIGMS notes. “These technical advances and abundance of sequencing data have opened opportunities for an entirely new approach to natural products discovery that overcomes current limitations. Now it is realistic to use the genomic information to infer the structure of natural products and to leverage advances in synthetic biology to engineer model microorganisms for the production of natural products. This initiative seeks to rapidly expand the pool of natural products by addressing technical and knowledge barriers to the development of genome-based natural products discovery approaches that can take advantage of advances in synthetic biology and the wealth of genomic and metagenomic data being generated across the world.”

Jeffrey Bouley

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