Natural Products

Natural products remain an important source of novel active compounds for use in human therapeutics, animal health, agritech and crop care . These are typically small molecules produced by microorganisms. The team at Isomerase are experts at working with microbial natural products produced by a wide range of microbes. Modern Natural Product discovery and development is aided by the use of modern biotechnology methods including genome editing and bioinformatics (for example genome sequencing and analysis) which are powerful tools enabling the discovery and development of a new generation of improved products.

We are experienced at setting up and managing natural product discovery projects with novel isolated strains, strains from our own strain collection (>30,000 isolates), public strain collections or initiating research on partially or fully isolated microbial natural products. We are able to engineer microbes to produce higher titres of the target natural product, remove competing natural products or generate analogues with favourable properties. 

We have proprietary technologies that allow us to manipulate natural product biosynthetic pathways and enzymes to produce novel analogues and our areas of particular expertise include; sterols, ribosomal peptides , non-ribosomal peptides, sterols, polyketides and proteins.

Natural Product Classes

We have experience working with a wide variety of natural product biosynthetic pathways including:

• Ribosomal peptides – These include both Ribosomally-encoded Post translationally modified peptides (RiPPs) and those produced by our own proprietary system in E.coli or Pichia.
• Non-ribosomal peptides – These peptides are produced by modular enzymatic systems and can include non-natural amino acids and N-methylation. Examples include vancomycin, indigoidine and epothilone. 
• Proteins – We have a range of technologies for the production of proteins (such as enzymes for biocatalysis) from a range of chassis strains, such as proprietary strains of E.coli, Pichia and Streptomyces.
• Polyketides – These are usually produced by similar modular enzymatic systems to the non-ribosomal peptides and are related to fatty acid biosynthesis but with extensive ability to alter the levels of processing and substitution within each module. They can also be produced by iterative systems. Examples include rapamycin, erythromycin, rifamycin, avermectin, amphotericin and doxycycline.
• Lipopeptides – These include natural products where a lipidic group is attached to a peptidic system, such as daptomycin and subtilisin.
• Steroids and sterols – Steroids are derivatives of the triterpene squalene. Includes sterols such as cholesterol and ergosterol and the broader class of steroids.
• Terpenes or terpenoids – include monoterpenes such as limonene or pinene, sesquiterpenes, such as farnesene and geosmin, diterpenes such as taxadiene (taxol precursor) and more complex terpenes such as triterpenes like squalene (precursor to steroids).
• Glycosylated products – These include natural products where there are one or more glycosyl groups. Examples include erythromycin, where two glycosyl groups are joined to a cyclic polyketide, vancomycin, where glycosyl groups are joined to a cyclic peptide and aminoglycosides, which comprise amino-modified glycosides such as kanamycin, neomycin and streptomycin. 

Natural product expertise

Microbial strains - We are skilled at working with both wild-type and genetically modified microbial strains producing a wide range of microbial natural products, including unicellular and filamentous fungi, and a wide variety of Gram-positive and Gram-negative bacteria. See some examples of our strains.

Pathway engineering - We can also build and optimise biosynthetic pathways in industrial strains to make a new related natural product or more of an existing product of interest. We can then ferment and isolate material from these strains and supply these to the partner from milligram to kilogram quantities

Chemistry - Our expertise in handling these types of complex chemistry also makes us well-suited for handling other natural product systems and products of complex synthesis. We have managed totally synthetic programs for a number of collaborators, designing targets, carrying out quality control, analytical and isolation chemistry and project management.

Natural Product discovery and sourcing

We have carried out many projects to access microbial natural products for partners from a variety of industrial sectors – including the production of compounds that are difficult to source or the isolation of novel natural products.

Example case studies are shown below:

• Research and find potential natural product producers in strain and patent collections
• Source known organisms from the Isomerase, public or patent culture collections
• Find novel natural products using in-house bioinformatic  searches using public genomic data or directly sequence and analyse the biosynthetic potential of genomes of potential producer organisms or metagenomes.
• Find similar natural product analogues through literature and bioinformatic searches
• In-house bioinformatics methods to predict proteins , peptides and biosynthetic gene clusters
• Synthetic biology and heterologous expression using in-house knowledge

Please contact us if you would like further information.