Fungal Sources of Bioactive Compounds in Your Medicine Cabinet

Stephanie Wright

Fungi have so many facets. Boletus edulus

Many of us like to eat macro-fungi fruiting bodies: mushrooms. We appreciate the fine flavors and textures they offer. Then there are the fungi that are more subtly connected to our menu, such as Penicillium glaucum that works to produce comestibles such as gorgonzola cheese.

[Tour cheesemaking operations or take classes, for information, see The Cheese Trail ]. Several species of Aspergillus are integral to the processes that make soy sauce and miso. Saccharomyces cerevisiae gives us cider, beer and wine, not to mention the bread consumed by much of the world's population as a staple food.

Mycorrhizal fungi may have been the key that enabled life to move onto land. 80% of plants species form mycorrhizas. Orchid seed germination is critically dependent on fungi.

On the less pleasant side, some species of fungi cause infections such as the annoying athlete's foot, and far more serious illnesses, particularly in immunocompromised individuals. But, this month, I want to share about a positive aspect of fungi that is easy to overlook - the contributions of fungi to our pharmaceutical armamentarium.

I'm guessing everyone remembers from elementary school the apocryphal story of the discovery of penicillin – careless lab technician leaves bread that gets moldy and kills bacterial culture… Well, it didn't happen quite that way…

Alexander Fleming was a experienced and well-respected microbiologist who coined the term lysozyme (lyso = cut, zyme = enzyme). Lysozyme is an essential component of our innate immune system. It is abundant in tears, saliva and breast milk.
At the time of the discovery, Fleming was actively searching for substances with Mold Cultures

antibiotic properties.

It was serendipitous that another lab in the same building was growing various mold strains one of which produced the almost magical chemical, later named penicillin, that eventually save millions of lives. Initially, it wasn't considered particularly important because it was quickly excreted from the person's body, was difficult to isolate, and there were no processes to produce enough of it to be significant for fighting the many infections that were common in the population.

In June, 1942, just 10 doses of penicillin existed in the world.
But the potential of the drug had been recognized following its use in a few “hopeless” cases. Early in WWII, enough people had been convinced, so that a project was launched to develop techniques and procedures to produce the life-saving antibiotic on an industrial scale. In 1945, nearly 8 billion doses were produced – that's impressive considering they started three years earlier knowing only how to make a tiny amount for experimental purposes.
For more about the history of penicillin, see:
1. [Northern Illinois University] Penicillin: Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois
2. [History Net] Penicillin: Wonder Drug of World War II

There are many more medicines that come from fungal origins. Sometimes a fungal derivative is used directly, other times a chemical produced by a fungus is used as a starting material for synthesis of more targeted drugs.

Many varieties of edible fungi might be considered potentially beneficial for health. Plus, there are a number of fungi, edible and not, that are commonly for sale as extracts, with purported medicinal benefits. That is a big topic and not the focus of this article. Trametes versicolor

However, a good resource on this subject is Memorial Sloan-Kettering Cancer Center. They have a regularly updated web site that includes biochemical pathways, potential interactions, and links to research papers. There is a lot of ongoing research taking place with fungi, with the intent to validate or refute claims from traditional medical systems.
Ganoderma lucidem

An example of a very popular “medicinal” mushroom is Reishi (Ganoderma lucidum) - the Sloan-Kettering web site has quite a lot of information regarding reishi, including links to 48 published papers.

For this particular newsletter article I am focusing on several widely used medications that you might be surprised to know came from humble, fungal origins. Plus others that are in the research and development stage.
---
In addition to penicillin, other classes of antibiotics have fungal origins. As do drugs for autoimmune diseases, cancer, migraine and more...

Cephalosporins are widely used antibiotics. They were discovered in Acremonium, an aerobic mold found near a sewage outfall in a Sardinian harbor in the 1940s. [Acremonium strictum, a widespread saprotroph, produces some types of cephalosporins as a metabolite, but it can also cause fatal infections in immunocompromised individuals.]
Sparassis crispa contains sparassol, an antibiotic and antifungal.
Aphidicolin reversibly inhibits DNA replication in eukaryotic cells and some viruses, and induces apoptosis (programmed cell death) in HeLa cells (if you know the story of Henrietta Lacks and the immortal cells cultured from her cervical cancer, this discovery of induction of apoptosis suggests that aphidicolin might be useful in cancer). Extracted from Cephalosporum aphidicola.
In their natural form, illudins are highly toxic, however, they have selective toxicity to some types of cancer cells and might be developed into future cancer treatments. They come from Omphalotus species (such as Jack o'Lantern).
Cyclosporin, derived from Tolypocladium inflatum is used to suppress the immune system in organ transplants recipients, and also people with some autoimmune diseases. [Have Sjogren's syndrome or dry eye for other reasons? you might be using Restasis, which is cyclosporin. Cyclosporin is on the WHO list of essential medicines and is 195th most prescribed med in the US.]
Mycophenolate is used to prevent organ rejection for people with transplants. It is also used in some autoimmune diseases. Mycophenolate can be derived from the fungi Penicillium stoloniferum, P.brevicompactum and P. Echinulatum
Fungal ribotoxins are used in the development of immunotoxin anti-cancer drugs.
Ergot. Claviceps purpurea is an ergot fungi. Maybe you are thinking, isn't that where LSD comes from? The fungus does produce lysergic acid, which is a chemical precursor of LSD (lysergic acid diethyl amide). [This fungus deserves an entire article of its own.]
For this short article, the other medical uses of ergot are the focus. Drugs derived from ergot include those that are used to treat migraines, postpartum hemorrhage, Parkinson's disease, and pituitary tumors. There is recorded use of ergot by midwives 500 years ago.
Statins - that class of drugs is the #1 most prescribed in the US. The original statin (cholesterol lowering medication), lovastatin, came from Aspergillis terreus. Oyster mushrooms – Pleurotus ostreatus – contain a few percent of statins by dry weight. But since they are mostly water, you aren't likely to get a therapeutic dose from your dinner.

Research is ongoing with chemicals derived from fungi that may have uses to treat malaria, diabetes and cancer and more.

Sources: in addition to links to Wikipedia and other online articles for specific information, these articles have an overview.

[NIH] A Historical Overview of Natural Products in Drug Discovery, June 2, 2012
[PLOS Pathogens] Putting Fungi to Work: Harvesting a Cornucopia of Drugs, Toxins, and Antibiotics, Mar 13, 2014
[PhysOrg] Using fungi to search for medical drugs, Nov 26, 2019
[Studies in Natural Products Chemistry] Bioactive Fungal Natural Products Through Classic and Biocombinatorial Approaches

Images:

Image, Ascomycetes, Source: Dr. David Midgley, University of Sydney, Australia, licensed under Attribution-Share Alike 2.5 Generic License. No changes made. https://commons.wikimedia.org/wiki/File:Ascomycetes.jpg
All other images from Wikimedia Commons, free use under Creative Commons CC0 1.0 Universal Public Domain Dedication

Drug information - basic

Research - just a starting point if you want to do more in-depth reading


Fungal Sources of Bioactive Compounds in Your Medicine Cabinet Stephanie Wright Fungi have so many facets. Many of us like to eat macro-fungi fruiting bodies: mushrooms. We appreciate the fine flavors and textures they offer. Then there are the fungi that are more subtly connected to our menu, such as Penicillium glaucum that works to produce comestibles such as gorgonzola cheese. [Tour cheesemaking operations or take classes, for information, see The Cheese Trail ]. Several species of Aspergillus are integral to the processes that make soy sauce and miso. Saccharomyces cerevisiae gives us cider, beer and wine, not to mention the bread consumed by much of the world's population as a staple food. Mycorrhizal fungi may have been the key that enabled life to move onto land. 80% of plants species form mycorrhizas. Orchid seed germination is critically dependent on fungi. On the less pleasant side, some species of fungi cause infections such as the annoying athlete's foot, and far more serious illnesses, particularly in immunocompromised individuals. But, this month, I want to share about a positive aspect of fungi that is easy to overlook - the contributions of fungi to our pharmaceutical armamentarium. I'm guessing everyone remembers from elementary school the apocryphal story of the discovery of penicillin – careless lab technician leaves bread that gets moldy and kills bacterial culture… Well, it didn't happen quite that way… Alexander Fleming was a experienced and well-respected microbiologist who coined the term lysozyme (lyso = cut, zyme = enzyme). Lysozyme is an essential component of our innate immune system. It is abundant in tears, saliva and breast milk. At the time of the discovery, Fleming was actively searching for substances with antibiotic properties. It was serendipitous that another lab in the same building was growing various mold strains one of which produced the almost magical chemical, later named penicillin, that eventually save millions of lives. Initially, it wasn't considered particularly important because it was quickly excreted from the person's body, was difficult to isolate, and there were no processes to produce enough of it to be significant for fighting the many infections that were common in the population. In June, 1942, just 10 doses of penicillin existed in the world. But the potential of the drug had been recognized following its use in a few “hopeless” cases. Early in WWII, enough people had been convinced, so that a project was launched to develop techniques and procedures to produce the life-saving antibiotic on an industrial scale. In 1945, nearly 8 billion doses were produced – that's impressive considering they started three years earlier knowing only how to make a tiny amount for experimental purposes. For more about the history of penicillin, see: 1. [Northern Illinois University] Penicillin: Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois 2. [History Net] Penicillin: Wonder Drug of World War II There are many more medicines that come from fungal origins. Sometimes a fungal derivative is used directly, other times a chemical produced by a fungus is used as a starting material for synthesis of more targeted drugs. Many varieties of edible fungi might be considered potentially beneficial for health. Plus, there are a number of fungi, edible and not, that are commonly for sale as extracts, with purported medicinal benefits. That is a big topic and not the focus of this article. However, a good resource on this subject is Memorial Sloan-Kettering Cancer Center. They have a regularly updated web site that includes biochemical pathways, potential interactions, and links to research papers. There is a lot of ongoing research taking place with fungi, with the intent to validate or refute claims from traditional medical systems. An example of a very popular “medicinal” mushroom is Reishi (Ganoderma lucidum) - the Sloan-Kettering web site has quite a lot of information regarding reishi, including links to 48 published papers. For this particular newsletter article I am focusing on several widely used medications that you might be surprised to know came from humble, fungal origins. Plus others that are in the research and development stage. --- In addition to penicillin, other classes of antibiotics have fungal origins. As do drugs for autoimmune diseases, cancer, migraine and more... Cephalosporins are widely used antibiotics. They were discovered in Acremonium, an aerobic mold found near a sewage outfall in a Sardinian harbor in the 1940s. [Acremonium strictum, a widespread saprotroph, produces some types of cephalosporins as a metabolite, but it can also cause fatal infections in immunocompromised individuals.] Sparassis crispa contains sparassol, an antibiotic and antifungal. Aphidicolin reversibly inhibits DNA replication in eukaryotic cells and some viruses, and induces apoptosis (programmed cell death) in HeLa cells (if you know the story of Henrietta Lacks and the immortal cells cultured from her cervical cancer, this discovery of induction of apoptosis suggests that aphidicolin might be useful in cancer). Extracted from Cephalosporum aphidicola. In their natural form, illudins are highly toxic, however, they have selective toxicity to some types of cancer cells and might be developed into future cancer treatments. They come from Omphalotus species (such as Jack o'Lantern). Cyclosporin, derived from Tolypocladium inflatum is used to suppress the immune system in organ transplants recipients, and also people with some autoimmune diseases. [Have Sjogren's syndrome or dry eye for other reasons? you might be using Restasis, which is cyclosporin. Cyclosporin is on the WHO list of essential medicines and is 195th most prescribed med in the US.] Mycophenolate is used to prevent organ rejection for people with transplants. It is also used in some autoimmune diseases. Mycophenolate can be derived from the fungi Penicillium stoloniferum, P.brevicompactum and P. Echinulatum Fungal ribotoxins are used in the development of immunotoxin anti-cancer drugs. Ergot. Claviceps purpurea is an ergot fungi. Maybe you are thinking, isn't that where LSD comes from? The fungus does produce lysergic acid, which is a chemical precursor of LSD (lysergic acid diethyl amide). [This fungus deserves an entire article of its own.] For this short article, the other medical uses of ergot are the focus. Drugs derived from ergot include those that are used to treat migraines, postpartum hemorrhage, Parkinson's disease, and pituitary tumors. There is recorded use of ergot by midwives 500 years ago. Statins - that class of drugs is the #1 most prescribed in the US. The original statin (cholesterol lowering medication), lovastatin, came from Aspergillis terreus. Oyster mushrooms – Pleurotus ostreatus – contain a few percent of statins by dry weight. But since they are mostly water, you aren't likely to get a therapeutic dose from your dinner. Research is ongoing with chemicals derived from fungi that may have uses to treat malaria, diabetes and cancer and more. Sources: in addition to links to Wikipedia and other online articles for specific information, these articles have an overview. [NIH] A Historical Overview of Natural Products in Drug Discovery, June 2, 2012 [PLOS Pathogens] Putting Fungi to Work: Harvesting a Cornucopia of Drugs, Toxins, and Antibiotics, Mar 13, 2014 [PhysOrg] Using fungi to search for medical drugs, Nov 26, 2019 [Studies in Natural Products Chemistry] Bioactive Fungal Natural Products Through Classic and Biocombinatorial Approaches Images: Image, Ascomycetes, Source: Dr. David Midgley, University of Sydney, Australia, licensed under Attribution-Share Alike 2.5 Generic License. No changes made. https://commons.wikimedia.org/wiki/File:Ascomycetes.jpg All other images from Wikimedia Commons, free use under Creative Commons CC0 1.0 Universal Public Domain Dedication Drug information - basic Cephalosporins Cyclosporin Mycophenolate Ergot Lovastatin Research - just a starting point if you want to do more in-depth reading Sparassol Aphidicolin Illudin Fungal ribotoxins, Immunotoxins Production and characterization of a colon cancer-specific immunotoxin based on the fungal ribotoxin α-sarcin Immunotoxins: A Review of Their Use in Cancer Treatment
Mycena News - February