Biosynthesis Approach to Novel Bioactive Aminocyclitols

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Principal Investigator/Program Director (Last, first, middle): Mahmud, Taifo - 2 R01 AI61528-05A1 The C7N-aminocyclitols. a relatively new class of microbial secondary metabolites, have great potential to be developed as drug candidates for the treatment of various physiological disorders (e.g., diabetes), infectious diseases (e.g., influenza and HIV infections), and cancer. This is due to their resemblance to sugar moieties, which are widely involved in structural and physiological systems in all living organisms. In this application, we propose to study the biosynthesis of C7N-aminocyclitolcontaining natural products and to use the knowledge to develop pharmaceutically important leads via biosynthetic approaches. The study will be carried out using two structurally distinct models: (1) the C7N aminocyclitols present as a core unit of natural products, represented by the antifungal agent validamycin, in S. hygroscopicus; and (2) the C7N-aminocyclitols present as a glycon, represented by the antibiotic pyralomicin, in Nonomuraea spiralis. The long-term objectives of this study include developing new C7N-aminocyclitol-based drugs to treat infectious diseases and various physiological disorders, improving production yields and providing alternative production strategies of clinically important C7Naminocyclitol compounds, and providing insights about the occurrence and distribution of this class of natural products in nature. This application employs a multidisciplinary approach that utilizes cutting-edge technologies in molecular genetics, enzymology, and chemistry to access, utilize and manipulate C7N-aminocyclitol biosynthetic genes. Manipulation of genes directly involved in precursor formation and tailoring process will be used to create novel biologically active compounds. The study includes the cloning and elucidation of the biosynthetic gene clusters of validamycin and pyralomicin; and characterization of their key biosynthetic enzymes. The knowledge and methods that arise from these studies will also be widely applicable to expanding the chemical diversity of other families of bioactive natural products.