BIOSYNTHESIS APPROACH TO NOVEL BIOACTIVE AMINOCYCLITOLS

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DESCRIPTION (provided by applicant): The increase of multi drug resistance (MDR) among pathogenic bacteria and fungi towards currently used antibiotics coupled with the lack of effective and safe medications to combat various physiological and regulatory disorders such as autoimmune diseases (e.g., multiple sclerosis, amyotrophic lateral sclerosis, etc.) and cancer urgently require new drug discovery. The CTN aminocyclitols, a relatively newly recognized class of microbial secondary metabolites, has great potential to be developed as drugs for various physiological disorders and infectious diseases. This is due to their resemblance to sugar moieties, which are widely involved in various ways in structural and physiological systems in living organisms. In this application, we propose to study the biosynthesis of C7N aminocyclitol-containing natural products and to use the knowledge obtained to develop pharmaceutically important leads via biosynthetic-based structure modifications. The study will be carried out with three different compounds: (1) the antifungal agent validamycin (in S. hygroscopicus); (2) the antibiotic pyralomicin (in Nonomuraea spiralis); and (3) the anti-tumor cetoniacytone (in Actinomyces sp.). The long-term objectives of this study include developing new CTN aminocyclitol-based drugs to combat infectious diseases and physiological disorders, improving production yields and/or providing alternative production strategies of clinically important CTN aminocyclitol compounds, and providing insights about the occurrence and distribution of this class of natural products in nature. The approach employs molecular genetics, enzymology, and chemistry to access, utilize and manipulate CTN aminocyclitol biosynthesis genes that direct precursor formation and other genes involved in the tailoring processes to create novel biologically active compounds. The study includes cloning and elucidation of the biosynthetic gene clusters of validamycin, pyralomicin, and cetoniacytone; elucidation of the newly discovered 2-epi-5-epi-valiolone pathway; characterization of the key biosynthetic enzymes; and use the information obtained to create novel bioactive aminocyclitols. The knowledge and methods that arise from these studies will be directly applicable to expanding the chemical diversity in other families of bioactive natural products.