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Manufacture Small Molecules

Digging for Drugs

Natural products are known to be a promising source of new drugs – particularly antibiotics and antimalarials – but hunting through almost countless possibilities is resource intensive, so many pharma companies long since abandoned the search. Now, University of Illinois chemistry professor William Metcalf and microbiology professor Wilfred van der Donk have used genome mining to rapidly screen thousands of strains of bacteria for a specific gene that they believe is the equivalent of striking gold (1). And, in the process, they’ve discovered several new compounds with potential, including a pair of antibiotics and an antimalarial.

It’s fairly common to use genome mining to find new drugs, but Metcalf and van der Donk have been very specific in their search. “Bacteria are like bad-tempered micro-chemists; they synthesize toxic compounds in tiny amounts to use as a warning sign for others to stay away. One compound produced by actinomycyte bacteria, a phosphonic acid, was found to inhibit cell wall biosynthesis. This is a very good target for an antibiotic because it targets a metabolic pathway that is present in bacteria but absent in humans,” says Metcalf. But because bacteria make phosphonic acids in low volumes, they had likely been missed in previous drug-screening programs.

Metcalf knew that the PepM gene was responsible for phosphonic acid biosynthesis – so finding the gene in different strains of bacteria could lead to the discovery of new phosphonic acids. To increase the chances of finding viable strains, Metcalf needed an army of bacteria – and fortunately there was one nearby: “Our university is near the US Department of Agricultural research, who allowed us to use their collection of about 10,000 strains (the largest publically accessible collection of actinobacteria in the US). We screened this collection for the presence of the PepM gene, and we identified 278 PepM-containing strains.”

These 278 strains were each responsible for synthesizing about 60 – 80 different potential drug molecules. About seven strains synthesized molecules in sufficient amounts to be easily purified, resulting in the discovery of 13 new natural products so far – including two antibiotics and one antimalarial. One of the compounds identified is potent against three different types of common bacteria: Salmonella typhimurium, Escherichia coli and Staphylococcus aureus.

Metcalf says, “We’ve focused on antibiotics, but 30-50 percent of all drugs are natural products (many from bacteria) and our approach will apply to all of these molecules too. We could use this approach for anticancer drugs, or even apply it to other fields to develop new herbicides and pesticides. I’m hopeful we could discover every useful natural product out there!”

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  1. K-S Ju et al., “Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes,” PNAS, 112, 39, 12175–12180 (2015).
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