Genomic Technique Devised to ID Drug Candidates

From left: Wilfred van der Donk, first author and postdoctoral researcher Kou-San Ju, and William Metcalf (University of Illinois, Champaign)

8 September 2015. Researchers at University of Illinois in Champaign developed a technique using genomic tools to identify natural substances in bacterial strains with potential therapeutic properties. The team led by microbiologist William Metcalf and chemistry professor Wilfed van der Donk published its findings last week in Proceedings of the National Academy of Sciences (paid subscription required).

The Illinois team is seeking a faster and more systematic process for identifying promising drug candidates from a large pool of natural sources, that today requires tests on and examinations of extracts from individual compounds. In their paper, the researchers report on a technique they call genomic mining that systematically reviewed more than 10,000 actinomycetes, a type of bacteria, searching for phosphonates or phosphonic acids, natural signaling molecules with antimicrobial, antiviral, antimalarial, and herbicidal characteristics.

Because of these properties, phosphonates can be a good raw material for drug compounds. “Of the 20 previously known natural-product phosphonates, two are used commercially, one as a clinical antibiotic and one as an herbicide, says vand der Donk in a university statement, “and another one is now in clinical trials to treat malaria.”

In their paper, vanderDonk’s and Metcalf’s labs used high-throughput screening to analyze the genomes of the 10,000 microbes, looking for a specific gene known as pepM required to synthesize phosphonates. This analysis yielded 278 strains of actinomycetes with the pepM gene. The team then reviewed the 278 strains for the structure of their genomes, matching them against known compounds to discover new therapeutic candidates.

The results revealed a new pathway for production of phosphonates in these organisms, as well as 11 previously undescribed natural phosphonic acid products. One of the new discoveries is a compound the team calls argolaphos, an antibacterial candidate with potency against Salmonella typhimurium, Escherichia coli (E. coli), and Staphylococcus aureus, three major disease-causing microbes.

The researchers believe genomic mining can speed the drug discovery process with natural sources. Metcalf notes, “pharmaceutical companies would have done bioassays on extracts from all 10,000 species,” adding “It was very, very tedious and very expensive. That would have taken a large company with hundreds of people years, if not decades.”

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