Chemical products from natural sources, i.e. natural products, are an extremely diverse set of compounds with a seemingly infinite set of chemical structures and bioactivities. Many of these compounds are very successful pharmaceuticals, and the discovery of novel natural products is obviously of great importance. With some 50% of all drugs derived from or inspired by natural sources, the unknown molecules present in all the species of the world represent an incredible amount of untapped potential. It is estimated that there are tens of millions of bacterial species in the world biome. Even if only 1/100 of these species produces at least one novel natural product, there would be a huge reservoir of undiscovered molecules with potential medicinal value. Actinomycetes are known to produce over 80% of the natural products that have inspired commercially used antibiotics, and genome sequences show that they collectively provide the largest pool of secondary metabolites (1). Thus, actinomycetes are evolutionarily optimised to be producers of natural products, making them potentially the best production host for heterologous high-value compounds.
In TOPCAPI, we will exploit systems and synthetic biology approaches and the natural fabrication power of actinomycetes, to create optimised actinomycete cell factories, to produce high-value compounds.
We target two Actinomycete hosts, which have been studied in the great detail since the 1950s.
1) Streptomyces coelicolor, our primary chassis, is genetically the best characterised actinomycete species. Its genome was sequenced over a decade ago, and researchers in academia and industry have developed a diverse toolbox of methodologies and genetic tools for the efficient manipulation of this important microorganism. A few heterologous expression strains have been developed, the most important of which is S. coelicolor M1152, which is widely used by the natural products community (2) In TOPCAPI, we will further engineer and optimise S. coelicolor M1152, using the latest genetic engineering techniques to turn S. coelicolor into a true workhorse for the industrial production of an unlimited diversity of metabolites, with the potential for rapid transfer to the industrial environment.
2) Streptomyces rimosus,
the natural producer of oxytetracycline (OTC), is genetically tractable, though not as widely used as S. coelicolor. It is one of the fastest growing Streptomyces species, with a very simple morphology, growing in the shape of short filaments, which is important especially when growing in industrial-scale fermentation, and S. rimosus has been adapted to industrial environments to gain GRAS (Generally Recognised as Safe) status (REF 3). In TOPCAPI we will genetically engineer S. rimosus to produce target tetracycline analogs.
These host species will be characterised using systems biology approaches, applying integrated data analysis to transcriptomics and metabolomics experiments, combined with predictive mathematical modelling, to drive the rapid improvement of the microbial cell factories for industrial drug production using advanced metabolic and biosynthetic engineering approaches. At the same time, we will establish an expanded toolbox for the engineering of actinomycete bacteria as general cell factories for other high added-value compounds.
- Cimermancic P, et al., Cell (2014) 158:412-21
- Gomez-Escribano J. P, Bibb M. J, Microb. Biotechnol (2011) 4: 207-215
- Petković H et al., Microbiol Mol Biol Rev. 2006 Sep; 70(3):704-28. Review.