Combinatorial and Synthetic Biosynthesis in Actinomycetes

Abstract

Bioactive microbial metabolites represent powerful tools against both acute and degenerative diseases (96). One of the most significant fractions within these physiological active compounds is represented by the polyketides. Their pharmaceutical use takes place in a variety of applications including antibacterials, immunosuppressants, anticancer agents, antifungal drugs, cholesterol-lowering agents, and products against animal diseases. It is difficult to estimate the magnitude of their advantages, but the utility of natural products as sources of novel structures still possesses great potential. Thus, in the area of cancer, in the time frame from around the 1940s to 2006, over 155 small molecules were introduced, of which 73% were other than “synthetics”, with 47% being either natural products or directly derived there from (28). The overuse of antibiotics has caused bacteria to become resistant to common drugs. Multiple antibiotic-resistance has emerged as one of the top public health issues worldwide in the last few decades and has focused attention on the need of new antibiotics (116). Many natural products isolated from microorganisms or plants are growing in environmental niches (41, 54). Also marine niches have been explored and revealed new bioactive compounds (13). It seems that natural products are finely tuned for interacting with biological systems and receptor molecules. They are the result of billions of years of evolution and far surpass anything yet created by humans. For this reason they represent a superior source of drug candidates or biologically active lead compounds. However, natural products have not been optimized in evolution as clinical drugs, but rather for their biological functions useful to the producing organism (36). Due to their variable structures, natural products or derived compounds can fulfill chemical and genetic approaches for deciphering cellular processes that need not necessarily be a target for therapeutic intervention (125). One great obstacle for the discovery of new bioactive natural products includes the rediscovery of known compounds at a high frequency. Technical challenges associated with purification and structure elucidation of the metabolites from microbial fermentations are tricky and engage microbiologists and chemists. Nevertheless, due to an explosive growth of the sequenced genome number, the potential of molecular genetics tools together with high-throughput screening systems and other technical advances, natural-product drug discovery has received new support.