Proteomining: An Integrated Approach to Mine for Novel Bioactive Compounds Produced by Actinomycetes
The expression of natural products produced by bacteria fluctuate with growth conditions, with a close correlation between the compounds and the gene expression that encode their biosynthesis. Some of the most promising compounds are only expressed when cultured under specific conditions, and have therefore been missed in the traditional screening campaigns by BigPharma. These are also referred to as 'cryptic' natural products, often in association with antibiotic activity. An important step in the drug-discovery program is to identify the genes that are responsible for the production of the bioactive compound of interest. A method that allows the rapid linkage of biosynthetic machinery (and hence biosynthetic genes) to a compound of interest is crucial to obtain rapid insight into the nature of the observed bioactivity. This will speed up de-replication and drug discovery.
Researchers at Leiden University have developed an integrated approach to mine for novel bioactive compounds produced by bacteria (e.g. Actinobacteria, Bacilli, Burkholderia, Pseudomonas), that exploits the application of genome sequencing in combination with metabolite identification methods, activity assays and proteomics or RNAsequencing. This approach allows identification of product, bioactivity and protein, whereas the protein then connects directly to the genome. A unique selling point for the technology is that it allows fast coupling of the genome to the metabolome and vice versa, without requirement of any knowledge on the chemical structure of the bioactivity of interest. That means it can also be used to find the biosynthetic genes for molecules that have never been seen before. In summary, the researchers developed an integrated method, which they named Natural Product Proteomining (in short, Proteomining), that accelerates the identification of genes that are responsible for the production of any bioactivity in microorganisms, which can be measured and whose activity fluctuates with growth conditions. The application lies in two directions, namely (1) finding a biosynthetic gene cluster or enzyme for a given bioactive molecule; or (2) finding a bioactive compound encoded by a given biosynthetic gene cluster.
Details and State of Development:
Application for the identification of known antibiotics and other bioactive compounds (validation) has been demonstrated, from Bacillus and Streptomyces species.
1. Discovery of microbial natural products with detectable bioactivity
2. Discovery of the biosynthetic gene cluster for a given bioactivity of interest.
3. Specifically, discovery of natural products with application as antibiotic, anticancer agent, antifungal, as anthelminthic or with other detectable feature (could also just be a mass spec peak).
Leiden University welcomes both licensing and R&D partnering inquiries.
- Accelerated identification of novel bioactive compounds from bacteria
- Simultaneous identification of the responsible gene (cluster)
Luris reference numberS190111-5140-15025
Patented US 9,617,592.