Natural Products

Natural products

This program develops tools for yeast and actinomycete cell factories to produce any plant, fungal or actinobacterial natural product. The natural products will include natural food colors, antibacterial and antifungal therapeutics, pesticides, and plant-derived therapeutics.

The tools include high-throughput genome engineering and screening, innovative biosensors, metabolic modeling and machine learning, regulatory network reconstructions, and transporter characterization and engineering.

First and foremost, the program will develop new microbial cell factories to produce high-value chemicals, focusing on bioactives, colors, antioxidants and nutraceuticals with annual market potential in the hundreds of millions to billions of Euros.

Many natural bioactives and colorant products have not reached market because they could not be sourced in sufficient quantities. This means that many promising natural products never reached the market, and many applications have been lost as a result.

The technologies to be developed will ensure that more of these natural products can be produced in sufficient quantities for testing/approval and eventually for the market.

Bioactives from Yeast
Plants and fungi are a rich source of natural products. These natural products have found use in treating human and animal diseases, in improving human and animal health, and as natural pest control agents. Due to the complexities of the genomes of the natural producers, and challenges in genetically modifying and cultivating them, expression of the biosynthetic pathways in a microbial host is a well-known and industrialized route for their production. A yeast platform would enable easier production of the natural products themselves, and enable production of unnatural products that may be even more active than their natural counterparts as human or animal therapeutics, or pest-control agents for agriculture. The goal with this program is to develop a Saccharomyces cerevisiae (yeast) platform for production of natural fungal polyketides and non-ribosomal peptides, and for refactoring these pathways to produce unnatural products. The specific objectives of our work are to:

1. Develop efficient pathways for production of polyketide and non-ribosomal peptide precursors and refactor the genes encoding these pathways into the yeast genome,
2. Introduce numerous natural biosynthetic gene clusters from filamentous fungi into the precursor-engineered yeast to produce the corresponding products, and
3. Refactor the natural biosynthetic gene clusters to produce unnatural polyketides, non-ribosomal peptides, and hybrid polyketides—non-ribosomal peptides. Because yeast is a well-known industrial organism, having it as a platform for refactoring natural and unnatural product pathways will allow relatively easy scale-up and large-scale production.

Bioactives from actinomycetes
Actinomycetes are among the most prolific producers of bioactive secondary metabolites and are the biological source for many important antibiotics used to treat bacterial infections.

Recent progress in whole genome sequencing-based genome mining technologies, improved methods for metabolic engineering of actinomycetes, such as CRISPR-based tools and strategies to integrate multi-omics datasets offers new possibility to access this huge and largely underexplored potential.

Enzyme biocatalysts for the industrial production of natural products
This part of the Natural Products program develops enzymes for biocatalysis, and pursue this goal with a particular focus on enzymatic glycosylation of natural products as a tool to control solubility, volatility, stability, compartmentalization, and toxicity.