CR2025_07 Secondary metabolic gene evolution in the industrially important fungi

Lead Supervisor: Dan Eastwood, Department of Biosciences, Swansea University

Email: d.c.eastwood@swansea.ac.uk

Co-supervisors: Claudio Greco, Department of Biosciences, Swansea University; Torda Varga, Royal Botanic Gardens, Kew.

Where will the next generation of biotherapeutics come from? Why have certain secondary metabolic pathways evolved in some fungi and not in others? How do environmental factors drive secondary metabolic diversity and production?

Fungi occupy diverse ecological niches and can grow as pathogens, saprotrophs or mutualists. Fungi also release an array of enzymes and secondary metabolites during their development or when colonising a new source of nutrition¹. The ecological function of some of these compounds is known to enhance the acquisition of nutrition (e.g. organic acids), protect cells (e.g. oxalate), and inhibit or harm other organisms (e.g. antimicrobial compounds), while many other functions are not characterised (e.g. toxins associated with poisonous mushrooms). The study and discovery of secondary metabolite diversity and their ecological role on other species is becoming increasingly accessible through high throughput sequencing and analytical technologies^2,3. Importantly, how chemical diversity influences the ecological function and life history of species is largely unexplored in fungal ecology.

Fungi within the Hypocreales and Polyporales are commonly found in nature and demonstrate diverse life histories (pathogens, saprotrophs, plant associates), while some species also have significant industrial potential. In the Hypocreales, Metarhizium species are important pathogens of insect pests used as biocontrol agents in farming and have been shown to improve plant growth as colonising endophytes and rhizosphere community members⁴. Closely related taxa, e.g. Trichoderma, are saprotrophs and pathogens of other fungi, some strains are used in pest management, while others impact the mushroom industry negatively⁵. Polyporales comprise wood-rotting species and medicinal mushrooms (e.g., Reishi), producing industrial and pharmaceutically relevant yet undescribed compounds⁶. The evolutionary mechanisms underpinning the diverse ecologies and interspecies interactions of these fungi are unknown. Understanding the evolution of biosynthetic processes would help develop better strains for integrated pest management, plant growth enhancement, biorefinery applications and the discovery of novel drugs as well as addressing how secondary metabolites impact the ecological function of these fungi. 

This project will focus on secondary metabolite evolution and is supported by an international research consortium currently sequencing the genome of 92 Hypocrealean fungal species and further by sequencing projects in the Royal Botanical Gardens, Kew. This project will aim to identify and characterise secondary metabolites associated with intraspecies interactions, whether harming insect or fungal hosts as pathogens, competing with other microbes, or mutualistically interacting with organisms. This project will conduct comparative genomics to determine the evolutionary emergence of secondary metabolites in Hypocreales and Polyporales with differing life histories. Further characterisation will identify secondary metabolites from selected fungi using chromatographic techniques aimed at identifying novel compounds with potential biotechnological and pharmaceutical applications.

The main scientific goals for this project will include:

• Gene mapping of proteins associated with secondary metabolic pathways in multiple fungi with diverse ecologies. Evidence of gene clustering or structural conservation (synteny) will be recorded.
• Phylogenomic assessment of secondary metabolite-associated proteins and trait-based assessment based on niche diversity and interaction biology. Specific consideration of core, conserved pathways in secondary metabolite biosynthesis and to what extent secondary product diversification is linked to trait evolution.
• High throughput chemical characterisation of genome-sequenced strains growing on standard media using HPLC-HRMS.
• More detailed chemical analysis of selected strains under a range of interaction scenarios to characterise active compound production and confirm predictions from phylogenomic trait analyses.
• An overall aim would be to identify secondary metabolic pathways that are associated with specific interaction ecology either as pathogens, mutualists or saprotrophs.

Training opportunities:

This project is embedded within the natural products and environmental resources research theme that has benefitted from >£1.2M investment in new laboratories and equipment, including HPLC-HRMS and analytical/preparative HPL-PDA/MS facilities that the successful candidate will be trained to use. Training will be provided on comparative genomic approaches and there will be opportunities to interact with other members of the Hypocreales genome programme to gain additional training if needed.

Student profile:

This project would be suitable for students with a degree in biology, ecology, microbiology, natural product chemistry, genetics or a closely related environmental or physical science. Bioinformatic background or programming language skill (R or Python) is an advantage.

References:

1. Keller NP. 2019. Fungal secondary metabolism: regulation, function and drug discovery. Nature Reviews Microbiology. 17: 167-180. https://doi.org/10.1038/s41579-018-0121-1
2. Theobald et al., 2018. Uncovering secondary metabolite evolution and biosynthesis using gene cluster networks and genetic dereplication. Scientific Reports. 8:17957. https://doi.org/10.1038/s41598-018-36561-3
3. Drott et al., 2021. Microevolution in the pansecondary metabolome of Aspergillus flavus and its potential macroevolutionary implications for filamentous fungi. PNAS. 118(21):e2021683118. https://doi.org/10.1073/pnas.2021683118
4. St. Leger RJ & Wang JB. 2020. Metarhizium: Jack of all trades, master of many. Open Biology. 10(12):200307. https://doi.org/10.1098/rsob.200307
5. Yao et al., 2023. Trichoderma and its role in biological control of plant fungal and nematode disease. Frontiers in Microbiology. 14:1160551. 10.3389/fmicb.2023.1160551
6. Quintero-Cabello et al., 2021. Antioxidant properties and industrial uses of edible polyporales. Journal of Fungi. 7(3):196. 10.3390/jof7030196