Fungal Drug Discovery for Chronic Disease: History, New Discoveries and New Approaches

Fungi have revolutionised medicine, yielding some of the most crucial pharmaceuticals in history. From the accidental discovery of penicillin in 1928 to the blockbuster statins that transformed cholesterol management, fungal-derived compounds have shaped modern healthcare. But as researchers exhaust conventional screening methods, new genomic tools and bioinformatics are opening up fresh opportunities for drug discovery.

A fascinating review from London Kew Gardens's research team published in Biomolecules (Prescott et al., 2023) delves into the past, present, and future of fungal drug discovery, highlighting approved drugs, clinical trials, and innovative approaches that could unlock the next generation of therapeutics.

Ophiocordyceps from Kew Garden's Fungarium. Image credits: Marc Violo

A History of Game-Changing Fungal Drugs

Fungi have provided key treatments for chronic infections, autoimmune diseases, and metabolic disorders. Penicillin, derived from Penicillium rubens, was the first antibiotic and remains one of the most important medical discoveries of the 20th century. It paved the way for cephalosporins, another major class of antibiotics originally extracted from Acremonium chrysogenum. These compounds revolutionised medicine, drastically reducing mortality from bacterial infections.

Antifungal drugs have also emerged from fungal sources. Penicillium griseofulvum produces griseofulvin, used to treat dermatophytic infections, while Aspergillus spinulosporus is responsible for echinocandins, a crucial class of antifungals that inhibit fungal cell wall synthesis and are often used for severe, resistant infections.

In the field of immunosuppression, Tolypocladium inflatum yielded cyclosporin A, a breakthrough drug that prevents organ transplant rejection by suppressing T-cell activity. Similarly, Penicillium brevicompactum produces mycophenolic acid, which inhibits lymphocyte proliferation and is widely used in combination therapies for transplant patients.

Statins, now among the most widely prescribed drugs globally, originated from fungi as well. Lovastatin, first isolated from Aspergillus terreus and Monascus ruber, effectively lowers cholesterol by inhibiting HMG-CoA reductase, the enzyme responsible for cholesterol biosynthesis. Mevastatin, from Penicillium citrinum, provided the foundation for synthetic statins like atorvastatin and simvastatin.

Fungi also produce neuroactive compounds, including psilocybin, the psychoactive molecule in Psilocybe mexicana and other psychedelic mushrooms. Currently in clinical trials, psilocybin is showing promise as a treatment for depression, PTSD, and substance use disorders, potentially offering a paradigm shift in psychiatric care.

Recent Discoveries and Clinical Trials

Despite past successes, finding new fungal-derived drugs has become increasingly difficult. However, some promising compounds are making their way through clinical trials.

Cordycepin, originally isolated from Cordyceps militaris, is under investigation as NUC-7738, a modified formulation with improved stability and bioavailability. Studies suggest it has strong anticancer properties, inhibiting tumour growth and metastasis by interfering with RNA synthesis.

Plinabulin, derived from Aspergillus species, is a potent microtubule polymerisation inhibitor currently in phase III trials. It is being tested as a treatment for chemotherapy-induced neutropenia, a common side effect of cancer treatment that weakens the immune system.

Irofulven, sourced from Omphalotus illudens, is another promising antifungal-derived compound with anticancer potential. It functions as a DNA alkylating agent, interfering with tumour cell replication, and is currently in trials for ovarian cancer and other malignancies.

Antroquinonol, extracted from Taiwanofungus camphoratus, has shown potential in treating lung cancer, liver disease, and even COVID-19. The compound modulates multiple metabolic pathways and inflammatory responses, making it a versatile candidate for drug development.

Recent fungal drug success stories. (A) Ophiocordyceps sinensis one of the sources of the compound cordycepin which has attracted significant attention from researchers leading to the investigative drug NUC-7738 for prostate cancer, photo credit to Lee Davies, RBG, Kew. (B) Endoconidioma carpetanum is an endophyte of juniper trees and source of the antifungal compound enfumafungin which led to the recently licenced antifungal drug ibrexafungerp. Photo credit Gerald F. Bills (C) Isaria sinclairii, emerging from its insect host. This species is one of the sources of the immunosuppressant compound myriocin which inspired the blockbuster multiple sclerosis drug fingolimod, photo credit to Lee Davies, RBG, Kew. (D) Psilocybe mexicana is the original source of the compound psilocybin which in 2018 was granted breakthrough therapy status by the Food and Drug Administration for treatment-resistant depression.

How Do Fungi Produce So Many Bioactive Compounds?

Fungi have evolved to synthesise powerful bioactive molecules to compete in their ecosystems. Many fungal drugs originate from self-defence mechanisms, targeting bacteria, competing fungi, or even insect hosts. Interestingly, several fungal metabolites inhibit enzymes conserved between fungi and humans, leading to unintended but beneficial effects in medicine.

Lovastatin, for example, blocks HMG-CoA reductase, a key enzyme in fungal cell membranes—but in humans, the same enzyme plays a role in cholesterol synthesis, making statins highly effective for cardiovascular disease prevention.

Cyclosporin A, originally evolved to suppress fungal calcineurin activity, turned out to be an exceptional T-cell inhibitor, preventing immune system attacks on transplanted organs and reducing autoimmune inflammation.

Mycophenolic acid, another immunosuppressant, was first discovered as a fungal compound that disrupts purine synthesis. In humans, this same pathway is essential for lymphocyte activation, making it an effective drug for transplant patients and those with autoimmune disorders.

Distribution of fungal orders across the fungal kingdom that have been reported to produce different categories of bioactive compounds, each represented in fungal orders. The data indicate that either research efforts are biased towards certain orders or that certain orders are particularly capable of producing bioactive compounds. (Dark blue) fungi that are believed to be psychoactive based on their traditional use or the presence of key metabolites, taken from Guzman et al. [2]. (Yellow) fungi that are recorded as the source of approved drugs, drug precursors or lead compounds in clinical trials phase 0 to 4 in the ChEMBL database as of 2021. (Green) antifungal compounds reported in the Journal of Antibiotics between the years 1961 to 2003. (Light blue) antibacterial compounds reported in the Journal of Antibiotics between the years 1961 to 2003. (Orange) all fungal secondary metabolites reported in the literature in 2020, taken from the Natural Product Atlas database.

The Future: Fungal Genomics and AI-Driven Discovery

New biotech companies like Hexagon Bio are using genomic tools to predict and isolate fungal drug candidates more efficiently. By identifying self-resistance genes, researchers can anticipate a compound’s mechanism of action before even isolating it. This targeted approach helps uncover new antibiotics, antifungals, and even cancer drugs much faster than traditional screening methods.

Beyond genomics, advances in heterologous expression systems—where fungal genes are transferred to model organisms like Saccharomyces cerevisiae—allow scientists to produce and study rare fungal compounds without relying on slow-growing or hard-to-culture species.

Where to Search for the Next Fungal Drugs?

Not all fungi are equal when it comes to drug discovery. Some taxonomic groups are particularly rich in bioactive metabolites:

The Ascomycota phylum, which includes Penicillium, Aspergillus, and Acremonium, has historically been a major source of antibiotics, antifungals, and cholesterol-lowering drugs. These species thrive in diverse environments and exhibit remarkable secondary metabolism capabilities.

Basidiomycota fungi, including Ganoderma, Psilocybe, and Omphalotus, are known for their neuroactive and immune-modulating compounds. Their bioactive molecules are being studied for applications in mental health, cancer, and immunotherapy.

Endophytic fungi, which live symbiotically inside plants, offer a relatively unexplored frontier for drug discovery. Some species, like Taxomyces andreanae, have been found to produce taxol-like compounds, raising questions about whether fungi might be an overlooked source of plant-associated medicinal molecules.

Fungi remain an untapped reservoir of potential new medicines. With modern sequencing, AI-driven analytics, and advances in heterologous expression systems, researchers are poised to unlock fungal metabolites that could combat antibiotic resistance, cancer, and neurodegenerative diseases. The next penicillin moment may be just around the corner.