Medicine

Fungal Genomic Breakthrough Unlocks a ‘Gold Rush’ of New Drug Discoveries

Fungi, long known as rich sources of natural molecules for drugs, could soon give up their molecular secrets via new technology that unlocks their genomes.

Several common medications, from the antibiotic penicillin to the LDL cholesterol-lowering drug lovastatin, originated in molds. Through the 1960s, molds and other fungi were at the center of largescale drug discovery, but then researchers hit roadblocks and the effort somewhat fizzled. Problems included challenges associated with culturing microbes in labs and isolating potentially useful molecules.

Now a technological breakthrough, outlined in a paper published by the journal Nature Chemical Biology, has just been developed that could unlock the floodgates for new drugs originating from fungi. The process involves using genomics and data analytics to capture fungal DNA and then identify promising new chemical molecules that could become the basis of a range of new drugs.

“New chemical matter from the fungal world can now be extracted,” senior author Neil Kelleher, a chemical biologist at Northwestern University, told Seeker. “So it’s like mining for gold, but instead of small labs panning for nuggets, the process can now be industrialized.”

The technology developed by Kelleher, lead author Kenneth Clevenger, and their colleagues consists of a three-step system. First, genomics and molecular biology are used to identify and capture broad portions of fungal DNA known as gene clusters. Next, the gene clusters are placed into a model fungus: Aspergillus nidulans.

Clevenger explained that this fungus “is one of the most studied fungi out there, so we know a lot about it biology and chemistry.” As a result, he continued, scientists can then distinguish with greater ease new molecules from those in the fungus that are already well documented.

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The final step is to utilize mass spectrometry and data analytics to analyze the resulting fungal compounds.

The researchers applied the three-step technology to investigate three diverse fungal species, and discovered 17 new compounds from the 56 gene clusters that they screened. Kelleher noted that this is “a great hit rate in the business of natural products discovery.”

The team named one of the new metabolites valactamide A, and it is now the focus of additional study. Co-author Nancy Keller of the University of Wisconsin-Madison said that fungi often produce such metabolites as protectants and weapons from other microbes or environmental stresses.

“Due to these properties,” she said, “many fungal metabolites become very valuable in treating human disease by targeting pathogenic microbes or malfunctioning human enzymes.”

Keller explained that fungi have complex cells like humans do and share many of the same proteins. As a result, they can interact with our bodies and change substances, such as enzymes.

For example, the fungi-sourced lovastatin targets an enzyme — HGM-CoA reductase — found in both humans and fungi. This enzyme is needed to produce cholesterol in humans as well as the fungi version of cholesterol, called ergosterol. When lovastatin interacts with the enzyme in a person, it can lower that individual’s LDL cholesterol (popularly known as the “bad” cholesterol). The drug also has antifungal properties.

“It’s likely that many fungi-sourced compounds with medical potential will be antimicrobial, but based on past history, we can also expect drugs to target the human immune response and high cholesterol, among others,” Clevenger said.

Other tech advances in recent years have led to the realization that good health often has more to do with a well-balanced microbiome than the presence — or absence — of any particular supposed beneficial or detrimental agent.

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For example, the bacterium Propionibacterium acnes — long associated with acne, as its name suggests — is actually the most prevalent and abundant bacterial species in the facial hair follicles of people with clear, healthy skin. Scientists are therefore rethinking conventional medical treatments as they proceed with new drug discovery.

“By finding a new generation of highly specific antibiotics, we can fight infection without carpet bombing our guts with broad spectrum drugs that wipe out large swaths of our microbiome,” Kelleher said. “We’ll need lots of different types of compounds, which we expect fungi will have since they’ve been fighting bacteria since long before humans walked the earth.”

The research team includes Chengcang Charles Wu and other scientists from the biotech company Intact Genomics, which has ambitious goals. As Wu put it, the company hopes “to help feed the world and to cure all human diseases through partnerships with individuals [and] private and public institutions.”

In terms of drug discovery, he and his colleagues believe that the newly developed three-step investigation process can be used to process close to 1000 fungi that potentially hold a wealth of beneficial molecules.

“Extrapolating from our study,” Kelleher said, “we could pull out something like 10,000 to 20,000 new types of drug-like chemicals in the next few years.”

WATCH: The Medical Promise of Fungus