Antibiotics are medicines used to prevent bacterial infections in both human and animals. Development and spread of antibiotic resistance is a universal threat to global health and food security and search for new and improved drugs is of high importance. Bacteria are a rich source of natural products with diverse chemical structures and functions; 43% of biologically active compounds originating from bacteria were isolated from bacterial species named Streptomyces. Production of the cell components (e.g. proteins, lipids, carbohydrates) that are vital for bacteria survival is named primary metabolism, whereas production of biologically active compounds (antibiotics, hormones, etc.) is named secondary metabolism. Bioengineering is a leading approach in the diversification of bacterial secondary metabolites. The aim of the project was to get the detailed understanding how Streptomyces are using a new pathway for generation of unusual building blocks that are used to assemble natural products and how scientists can use the pathway for production of new antibiotics. The key enzymes of the pathway are highly similar to those that are involved in fatty acid biosynthesis (primary metabolism) and typically are not found in secondary metabolism. The project was divided into the following parts: (a) to find additional examples of the new pathway by targeted genome sequencing and confirm the pathway identity by gene knock-outs; (b) to study the candidate enzymes from the pathway in vitro for their substrate specificity and ability to accept non-natural substrates bearing chemical functionality; (c) to generate a new derivative of a well-studied antibiotic using the newly identified pathway in vivo. Production of non-natural antibiotics will provide an attractive way both to tag antibiotics for target identification studies, and to generate novel analogues of the parent molecule as potentially valuable leads in drug discovery. This approach to extender unit alteration sufficiently contributes to the panel of tools used for targeted modification of pharmaceutically important natural products, as well as for overall competence of European science.
