Weekly News

Technology unlocks mold genomes for new drugs

June 12,2017 17:31

Now scientists at Northwestern University, the University of Wisconsin-Madison 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 ...and more »

June 12, 2017

Credit: Susan Buck Ms/Public DomainFungi are rich sources of natural molecules for drug discovery, but numerous challenges have pushed pharmaceutical companies away from tapping into this bounty. Now scientists at Northwestern University, the University of Wisconsin-Madison 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," said Neil L. Kelleher, a chemical biologist at Northwestern. "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."
Kelleher is the Walter and Mary E. Glass Chair in Life Sciences in the Weinberg College of Arts and Sciences and director of the Proteomics Center of Excellence.
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 millennia of evolution—for new drug leads. These small molecules could lead to new antibiotics, immunosuppressant drugs and treatments for high cholesterol, for example.
For four years, Kelleher has collaborated with Nancy P. Keller, the Robert L. Metzenberg and Kenneth B. Raper Professor of Mycology at Wisconsin, and colleagues at Intact Genomics in St. Louis on developing the technology, called FAC-MS (Fungal Artificial Chromosomes with Metabolomic Scoring).
In 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."
The study will be published June 12 by the journal Nature Chemical Biology. Kelleher, Keller and Chengcang C. Wu of Intact Genomics are the corresponding authors of the paper.
"Fungi make these natural products for a reason, and a lot of them are antimicrobial," said Keller, professor of medical microbiology and immunology and bacteriology at Wisconsin. "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 Northwestern-Wisconsin-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," said Kenneth D. Clevenger, who is a National Institutes of Health National Research Service Award Postdoctoral Fellow in Kelleher's 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," said Jin Woo Bok, a senior scientist in Keller's lab at Wisconsin and a first author of the study.
If brought to an industrial scale, the new FAC-MS process will help domesticate wild molds to reinvigorate drug discovery with compounds from the natural world.
Explore further: Biosynthetic secrets: How fungi make bioactive compounds
More information: "A Scalable Platform to Identify Fungal Secondary Metabolites and Their Gene Clusters," Nature Chemical Biology (2017). DOI: 10.1038/nchembio.2408

Biosynthetic secrets: How fungi make bioactive compounds

Biological engineers at Utah State University have successfully decoded and reprogrammed the biosynthetic machinery that produces a variety of natural compounds found in fungi.

Scientists engineer baker's yeast to produce penicillin molecules

The synthetic biologists from Imperial College London have re-engineered yeast cells to manufacture the nonribosomal peptide antibiotic penicillin. In laboratory experiments, they were able to demonstrate that this yeast ...

CRISPR mines bacterial genome for hidden pharmaceutical treasure

In the fight against disease, many weapons in the medicinal arsenal have been plundered from bacteria themselves. Using CRISPR-Cas9 gene-editing technology, researchers have now uncovered even more potential treasure hidden ...

New study sets the stage for engineering fungi to make fuels instead of toxins

Molds produce a wide range of both valuable and toxic molecules, which have important implications for energy production, agriculture and human health. A recent study revealed that an organelle within fungal cells called ...

Fungi have enormous potential for new antibiotics

Fungi are a potential goldmine for the production of pharmaceuticals. This is shown by researchers at Chalmers University of Technology, who have developed a method for finding new antibiotics from nature's own resources. ...

A novel roadmap through bacterial genomes leads the way to new drug discovery

For millennia, bacteria and other microbes have engaged in intense battles of chemical warfare, attempting to edge each other out of comfortable ecological niches. Doctors fight pathogens with an arsenal of weapons—antibiotics—co-opted ...

Promiscuous salamander found to use genes from three partners equally

A promiscuous salamander has found a simple genetic formula for success: Mate with multiple males and use equal parts of each partner's genetic material in her offspring.

Rattling DNA hustles transcribers to targets

Imagine if a dense thicket didn't obstruct your path but instead picked you up and shuttled you through the forest. That's what tightly packed DNA might be doing with important life molecules to get them where they're needed ...

Islands and coastal regions are threatened the most

Humans are responsible for the movement of an increasing number of species into new territories which they previously never inhabited. The number of established alien species varies according to world region. What was previously ...

A single molecule is missing and the cell world is empty

Cells multiply by duplicating themselves: they grow, replicate their components, and finally split into two. Many diseases are related to defective cell division; cancer is one of them. Understanding mechanisms conducting ...

Uncovered: 1,000 new microbial genomes

The number of microbes in a handful of soil exceeds the number of stars in the Milky Way galaxy, but researchers know less about what's on Earth because they have only recently had the tools to deeply explore what is just ...

Detailed new genome for maize shows the plant has deep resources for continued adaptation

A new, much more detailed reference genome for maize, or corn, as it is called in the U.S., will be published in Nature today. In its accounting of the sequence of DNA letters in the plant's 10 chromosomes, the new version ...

Physics News,Science news,Technology News,Physics,Materials,Nanotech,Technology,Science

Share this article

Related videos

2017 Killian Lecture: Eric Lander,
2017 Killian Lecture: Eric Lander, "Secrets of ...
"The Hidden Path to Creativity" | Stephan Schwa...