engleski

Novel hybrid polyketide therapeutics made by metabolic engineering

Streptomyces species have enormous potential for the biosynthesis of chemically diverse polyketide structures with a broad spectrum of biological activities (Nisbet, Ciba Symp., 171: 215, 1992). For that reason this project aims to construct genetically modified strains of Streptomyces rimosus capable of generating novel chemical entities of potential therapeutic value which are based on the carbon skeleton of aromatic polyketide antibiotic oxytetracycline (OTC). This species has been already used in Croatia for a long time to make OTC (e.g. Hranueli et al., Food Technol. Biotechnol. Rev., 33: 51, 1995). Our understanding of biosynthesis of bioactive metabolites by streptomycetes has recently improved substantially, especially the generation of novel therapeutics by this route is a viable proposition (Khosla & Zawada, Trends Biotechnol., 14: 335 1996). During the proposed research, some otc genes of S. rimosus will be inactivated by homologous recombination and replaced by heterologous genes from other streptomycetes that synthesise related but chemically different polyketide structures. It is expected that the constructed strains will be capable of biosynthesising novel, 'hybrid', chemical entities. Novel hybrid products will be isolated, characterised chemically and screened for biological activities that could form the basis of new therapeutics. For the efficient construction of genetically modified strains of S. rimosus, further analysis of its genome structure and stability are planed. Besides, we started the study of S. rimosus physiology and its behaviour in biotechnological processes as well as the study of specificity and kinetics of enzymes involved in OTC resistance, by studying enzyme/substrate crystal complexes, including their ability to accept novel substrates.

Streptomyces; polyketide; novel chemical entities

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