Hypocrealean fungi are useful biocontrols. They are sometimes applied to crops to protect them against pests or other microorganisms. Despite their utility, scientists don’t have a good understanding of what compounds make these fungi effective.
Now, Pablo Cruz-Morales, a biochemical engineer at the Technical University of Denmark, and his team have described a good chunk of the compounds that Hypocreales fungi produce, thanks to the use of some innovative tools (Nat. Chem. Biol. 2026, DOI: 10.1038/s41589-026-02201-5).
Cruz-Morales says that pests can cause losses “up to 40% of the global crop production” and better pest control methods are urgently needed. Biocontrols present an enticing alternative to traditional pesticides, but right now, “they’re not that reliable,” he says.
In the hopes of better understanding the fungi, Cruz-Morales and his team set out to find what compounds these fungi actually produce. To do that, the researchers used genome-mining tools to uncover biosynthetic gene clusters across 82 Hypocreales species, and then they grew each species using four different cultivation methods to induce production of a diverse array of secondary metabolites.
Most of the discovered compounds, the team found, were products derived from nonribosomal peptide synthetases, including “diketopiperazines, cyclic depsipeptides, and linear peptides.” Cruz-Morales says that most of these are small and basic, made of repeating units of a single amino acid or hydroxy acid. But some of the less common compounds discovered were more complex.
“There are some that are extraordinarily large peptaibols,” Cruz-Morales says. “Those are 18-member peptides, for instance, in Trichoderma. And other species like Tolypocladium also have this type of products, and their distribution is very narrow within a subgroup of this species.”
The team also discovered some compounds not previously reported to be made by Hypocreales fungi, and they were able to link those compounds to biosynthetic gene clusters. But the majority of biosynthetic gene clusters still aren’t linked to the products they make.
Seogchan Kang, a fungal biologist at Pennsylvania State University, praises the work and says that it “really provided a foundation that we can apply to understand the biology of other fungi.” Specifically, Kang believes that comparing Cruz-Morales’s data on biocontrol fungi with data on nonbiocontrol fungi might help us better understand what makes some fungi beneficial.
Cruz-Morales says that the team isn’t ready to prioritize turning some of the compounds they found into agricultural products. Instead the goal is to “maximize the number of molecules that we can get and to lower the cost of discovery.”
The hope is that other labs will be able to adopt this method and broaden the world of natural products that molecule developers get to explore. “The scale and the base of the discovery needs to go faster, and the key for that is to be cheaper,” Cruz-Morales says.
CORRECTION
This article was updated on May 6, 2026, to correct the description of compounds discovered in fungi. Pablo Cruz-Morales said some are large peptaibols, not peptide balls.
2026 American Chemical Society
