Discovery and biosynthetic investigations of NAD-derived natural products

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Natural products and their derivatives have significance as lead structures for drug development. They are generated by characteristic biosynthetic enzymes, which convert specific primary metabolites and produce the overall natural product carbon backbones. Members of canonical natural product classes, such as terpenoids, polyketides and non-ribosomal peptides are derived from oligoprenyl diphosphates, activated C2-building blocks like malonyl-CoA or amino acids. Besides these classical natural product families, it was recently shown that the central electron carrier nicotinamide adenine dinucleotide (NAD) acts as a building block for the biosynthesis of structurally unique isoleucyl-tRNA synthetase inhibitors. Bioinformatic analyses suggests, that novel NAD-utilizing metabolic pathways towards yet unknown NAD-derived natural products are encoded in Nature. The project aim is the identification and biosynthetic investigation of NAD-derived natural products. To achieve these goals, an isotope-guided untargeted metabolomics methods will be developed and applied. 13C-labeled biosynthetic precursors will be synthesized and utilized for feeding experiments to enable selective labeling of NAD-derived metabolites. In a complementary approach, a heterologous production platform will be established to enable product identification of silent biosynthetic gene clusters. Novel NAD-derived metabolites will be isolated and their structural and biological properties determined with a focus on antibiotic activity, based on resistance gene considerations (aminoacyl-tRNA synthetase inhibitors). The second aim of the project is the biosynthetic investigation of a selected gene cluster, focusing on the enzymology of the encoded PLP-dependent enzyme. The project will thus contribute to the investigation of the newly discovered NAD-derived natural product class, with the potential to discover novel antiinfectives, as well as unprecedented enzyme chemistries involved in their biosynthesis.