Fungi: a source for new drugs?

UTRECHT, The Netherlands—Researchers from Jeroen den Hertog’s research group at the Hubrecht Institute, in collaboration with researchers from the Westerdijk Institute and Utrecht University, have set up an enormous library derived from more than 10,000 fungi and screened it for biologically active compounds.

The researchers tested the biological activity of these fungal products first using zebrafish embryos. They chose zebrafish embryos because they allow the analysis of effects on many cell types at the same time, in a working body, and because zebrafish are physiologically similar to humans. An article explicating the results of this research was published today in Scientific Reports.

New therapeutic compounds are in constant demand in the clinic. Fungi are an excellent, but under-explored source of these kinds of compounds — such as lovastatin, a cholesterol lowering compound produced by the fungus Aspergillus terreus. The library of fungal products offers ample opportunity to search for new drugs.

“Every year new compounds produced by fungi are identified, but so far we have only investigated a very small subset of all existing fungi. This suggests that many more biologically active compounds remain to be discovered,” stated Jelmer Hoeksma, one of the researchers at the Hubrecht Institute.

The collaboration with the Westerdijk Fungal Biodiversity Institute, home to the largest collection of live fungi in the world, enabled the researchers to set up a large library of filtrates derived from more than 10,000 different fungi. A filtrate contains all the products that the fungus excretes.

To search for therapeutic compounds, the researchers investigated the effects of this library of fungal products on zebrafish embryos. Within a few days these embryos develop most of their organs, making biological activity of the fungal compounds readily detectable. And comparison to known drugs may result in identification of new drugs and point towards the underlying mechanisms of action of these compounds.

The researchers found 1526 filtrates that contain biologically active compounds with an effect on zebrafish embryos, from which they selected 150 filtrates for further analysis. From these, they isolated 34 known compounds, including lovastatin.

Researchers found filtrates that affect pigmentation in zebrafish embryos. Other studies have shown that factors involved in pigmentation can also play a crucial role in the development of skin cancer. The researchers are currently isolating the active compounds that cause pigmentation defects in zebrafish embryos from the filtrates.

“We believe there is a great potential in fungal filtrates, which cause reduced pigmentation, as they may lead to identification of compounds for future development into drugs to combat melanoma,” the article notes. “Currently, we are purifying compounds from this category in an attempt to establish the identity of active compounds.”

This study underlines the large variety of biologically active compounds that are produced by fungi, and the importance of further investigating these compounds in the search for new drugs.

“Taken together, the library of fungal mixtures that we generated expresses a diverse array of biologically active compounds, of which we have explored only a small part,” says the article. “This library is likely to contain many more distinct biologically active compounds. In fact, the library can be used in practically any assay for biological activity and therefore represents a great resource to uncover biologically active compounds.”

“The large library of fungal filtrates that we have set up can also be tested in many other systems, such as models for antibiotic resistance in bacteria and tumor development, making this study only the tip of the iceberg,” added Hoeksma.