Finding useful chemicals from fungi, faster

Fungi are rich sources of natural molecules for drug discovery, but many challenges have pushed pharmaceutical companies away from tapping into this bounty.

Now scientists at the University of Wisconsin–Madison, Northwestern University, and the biotech company Intact Genomics have developed technology that uses genomics and data analytics to efficiently screen for molecules produced by molds to find new drug leads — maybe even the next penicillin.

“Drug discovery needs to get back to nature, and molds are a gold mine for new drugs,” says Nancy Keller, a professor of medical microbiology at UW–Madison. “We have established a new platform that can be scaled for industry to provide a veritable fountain of new medicines. Instead of rediscovering penicillin, our method systematically pulls out valuable new chemicals and the genes that make them. They can then be studied in depth.”

Scientists believe there are thousands or even millions of fungal molecules waiting to be discovered, with enormous health, social and economic benefits. The new technology systematically identifies powerful bioactive molecules from the microbial world — honed through evolution — for new drug leads. These small molecules could lead to new antibiotics, immunosuppressant drugs, or treatments for high cholesterol, for example.

For four years, Keller has collaborated with Neil Kelleher, a professor of life sciences and director of the Proteomics Center of Excellence at Northwestern, and colleagues at Intact Genomics in St. Louis on developing the technology, called FAC-MS (Fungal Artificial Chromosomes with Metabolomic Scoring).

In the recent work, the researchers applied their refined method to three diverse fungal species and discovered 17 new natural products from the 56 gene clusters they screened with the new process. That’s a hit rate of 30 percent, which, Kelleher says, is “absolutely phenomenal.”

“Drug discovery needs to get back to nature, and molds are a gold mine for new drugs,”

Nancy Keller

The study is published Monday (June 12, 2017) by the journal Nature Chemical Biology. Keller, Kelleher and Chengcang Wu of Intact Genomics are the senior authors of the paper.

“Fungi make these natural products for a reason, and a lot of them are antimicrobial,” says Keller. “They’re used as weapons to kill or retard growth of other fungi, bacteria or any other competing microbe in the area where the fungus wants to grow. Fungal compounds are a major source of diverse drugs.”

Each of the three institutions has played a key role in developing FAC-MS. The three-step system uses genomics and molecular biology to identify and capture large swaths of fungal DNA, called gene clusters, that are very likely to produce new molecules of interest, puts the DNA in a model fungus that grows easily in the lab, and then analyzes the chemical products using mass spectrometry and data analytics.

Scientists using fungal species for drug discovery have recently faced a number of problems: the slow rate at which researchers can systematically unlock fungal compounds; the rediscovery of old compounds, such as penicillin; the difference between what a fungus could produce versus what it actually does; and the ability to know when you have a new chemical as opposed to the thousands of more mundane compounds cells produce.

The Wisconsin-Northwestern-Intact Genomics team worked to address these problems to greatly increase the throughput of identifying new chemicals and the gene clusters responsible for their production.

“Because these molecules are coming from a biological system, they tend to be more complex than a new molecule made in a pharmaceutical lab,” says Kenneth Clevenger, a postdoctoral researcher in the Kelleher lab at Northwestern and a first author of the study. “Molecules from fungi are predisposed to interact with cells and proteins, so, in that sense, they have promise. Our hope is that we find useful bioactivities that could lead to new medicines.”

The big advance in the Nature Chemical Biology study, the researchers say, is how many gene clusters they were able to wrangle in a single study. Instead of reporting just one or two, they teed up 56 gene clusters and pulled out 17 new natural products and picked one to rigorously characterize in depth, which they named valactamide.

“We’ve designed a methodology where we can take all 56 gene clusters from fungi, package them and go through a process where we can try to express all of them,” says Jin Woo Bok, a senior scientist in Keller’s lab at UW–Madison and a first author of the study.

If brought to an industrial scale, the new FAC-MS process could help domesticate wild molds to reinvigorate drug discovery with compounds from the natural world.

The work was supported in part by the National Institutes of Health (grants R44AI094885, AT009143, R01-AI065728 and 5T32GM105538-04).