A deep dive into the genomes of fungi

A treasure trove of medicinal compounds could still be lurking within the fungi that revolutionised modern medicine through the use of antibiotics, according to a new study published in Nature Microbiology.

Penicillin, derived from the Penicillium fungi, became the first mass-produced antibiotic in the 1940s. Antibiotics have since saved millions of lives, but their efficacy against bacterial infections is waning, due to rampant overuse leading to potentially catastrophic antimicrobial resistance. Some estimates predict 10 million human fatalities a year by 2050 due to antibiotic ineffectiveness.

Yet the answer to this nightmare scenario may well lie in remining the veins of the Penicillium fungi, which bio-prospectors hunting for the next pharmaceutical blockbuster have to date largely overlooked despite it also being the source of other useful drugs including cholesterol-lowering statins.

There are more than 300 species of Penicillium fungi – organisms found in everything from soil to cheese. The new work led by Jens Nielsen at Chalmers University of Technology in Gothenburg, Sweden, took a deep dive into the genomes of 24 of those species – nine newly sequenced for the study.

The researchers looked for gene clusters that provide blueprints for synthesising secondary metabolites, like penicillin. Secondary metabolites aren’t essential to a fungus’s growth and development but give it an edge in fending off other microbes, or when invading a plant’s tissues during infection, for example. Many secondary metabolites aren’t readily isolated from lab-grown fungi, because the cues needed to switch on production aren’t yet understood.

Genome mining gets around this.

By scanning for genes that make the core scaffolding of some common secondary metabolites, the researchers identified entire gene clusters containing instructions for enzymes that decorate the scaffolding. Each cluster did so in a slightly different way, producing diverse chemical structures.

The study netted more than 1,300 biosynthetic gene clusters across the 24 genomes, an average of more than 50 per species. About 250 were unique to a single fungal species.

The surprising number of secondary metabolite clusters identified, says Nielsen, “demonstrates the untapped potential of filamentous fungi”.

In about 90 cases, Nielsen’s team was able to predict the molecules the clusters made.

For one compound, an anti-fungal called yanuthone, the team connected the dots from gene cluster to product by identifying yanuthone in extracts from two species not previously known to produce it.

“This is a very exciting area of research,” says synthetic biologist Yit Heng Chooi from the University of Western Australia, who was not involved in the study. “The future of drug discoveries is definitely moving in this direction where we’re trying to use a more genomics-based approach to discover small molecules from micro-organisms.”

With so many gene clusters identified, Chooi says the challenge will be how to prioritise which pathways to study further.

Nielsen’s team can now transplant entire gene clusters into yeast cells to study the compounds they synthesise in a system free of other secondary metabolites. Enzymes from different clusters could also be mixed and matched to create molecules that don’t exist in nature, Nielsen says. “We’re just beginning to scratch the surface.”