Drug discovery and fungi have gone hand in hand since pharmacology emerged as a relevant science. As the decades have passed, it has become apparent to scientists that there is an untapped well of potentially useful chemicals that are naturally produced by the millions of fungal species on Earth. Chemicals such as these—that aren’t necessary for survival but often provide an evolutionary advantage to the organism—are known as secondary metabolites by microbiologists. These chemicals, the “armor and weapons” of fungi according to Nancy Keller, professor of Medical Microbiology and Immunology at UW-Madison, are responsible for some of the most effective drugs used today including antibiotics, antivirals, cancer drugs and cholesterol lowering drugs.
Keller is a principal investigator on a new study that came out in June along with Jinwoo Bok, also of UW-Madison, Neil Kelleher of Northwestern University and Chengcang Wu of the biotech company Intact Genomics. Keller, Bok, Kelleher and Wu have developed a faster and cheaper scalable pipeline to hunt for useful natural products from fungi.
At the core of their system are sections of fungal genomes that scientists call biosynthetic gene clusters (BGCs). BGCs contain the enzymes, regulatory elements and all necessary genes for a fungus to make a specific secondary metabolite. According to Keller, most species of fungi have dozens of these genetic units and as a result, dozens of potentially useful chemicals.
Historically, many difficulties have impeded screening this plethora of unknown chemicals. One such obstacle is that most fungi cannot be grown efficiently or under the same conditions as in nature in the lab.
“We just can’t mimic everything that’s happening in the environment,” Keller explains, so a fungus likely won’t actively produce its natural products in the lab.
The true value of this study is one of throughput, or the rate at which something can be processed or screened. The platform that the scientists developed—FAC-MS (Fungal Artificial Chromosome-Metabolic Scoring)—involves snipping out BGCs from the fungal genome in question and inserting them into a model fungus that grows well in the laboratory and can produce the secondary metabolites as instructed by the BGCs. This way, they can screen large numbers of natural fungal products at once and identify the specific species and BGC that makes the chemical.
Another key component of the system is a data analysis technique called Metabolic Scoring. After the compounds are produced by the model fungus, the team uses Metabolic Scoring to identify which chemicals are unique to each specific BGC. Previously, the confounding influence of all normal metabolites produced by fungi prevented them from connecting specific compounds to their biosynthetic pathways.
In short, the FAC-MS platform provides unprecedented access to the millions of fungal secondary metabolites that scientists know are out there but have until recently lacked an efficient method to isolate and characterize them.
But why do fungi produce chemicals that can be used to lower cholesterol, or suppress the human immune system, for instance, in the first place?
“This is sort of accidental actually,” Keller points out as she describes that molecules produced by fungi can interact with human proteins largely due to our shared eukaryotic genetic heritage. As an example, she explains why the drug Lovastatin, an essential cholesterol lowering drug that was discovered in fungi, works in humans:
“The fungus that makes Lovastatin, which is a statin, a cholesterol lowering drug, didn’t make it with the thought that some day a company is going to take it and grow it up and give it out to people with high cholesterol. This molecule targets an enzyme found in both humans and fungi. Humans need the enzyme to make cholesterol; fungi need the enzyme to make their analogous sterol called ergosterol. Lovastatin kills other fungi by inhibiting ergosterol production and the fungus that makes lovastatin has a second copy of the target enzyme which is presumably resistant to lovastatin.”
As a proof of concept for their platform, the researchers took 56 BGCs from three species of fungi through their pipeline and detected 17 secondary metabolites, 15 of which were previously unknown to scientists. Fifteen out of 56 is a remarkably high success rate for isolating novel natural products. This proves that the FAC-MS pipeline drastically decreases the time and resources required to discover new secondary metabolites. After initial discovery and identification, these compounds progress through many tests to confirm function and safety before entering final testing in clinical trials.
While FAC-MS only increases efficiency at the start of the drug discovery and development process, technologies like these have the potential to reinvigorate drug discovery in the 21st century. Discovery of new antibiotics has severely declined since life-saving drugs revolutionized medicine in the 20th century. As antibiotic resistant bacteria grow to be more and more of a global health crisis, discovering new antibiotics from fungi could benefit society immensely. The team of researchers designed this high-throughput technology with the intention of it being scaled up in industry to discover new drugs in an efficient manner. Keller, Bok, Kelleher and Wu’s collaboration serves as proof that there are new scientific revelations to be made out there, and that working together is the best way to pave a brighter future.
