Discovery, biosynthesis and bioactivity of phosphonic acid natural products

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Project Summary Phosphonic acids, defined by the presence of stable carbon-phosphorus (C-P) bonds, are an underexploited group of compounds with great biomedical promise, which stems from (1) a proven track record in clinical and commercial applications, (2) an immense diversity of cellular targets and modes of action (3) availability of a suite of research tools that allow facile discovery and characterization, (4) a proven reservoir of novel, unchar- acterized members of the class, and (5) unusual biosynthetic pathways whose characterization has enhanced and expanded our knowledge of fundamental biochemistry. This research project takes advantage of these fea- tures, focusing on phosphonate natural products with useful bioactivities and interesting chemical features, as well as the discovery of novel phosphonates. The long-term goals of the project include elucidation of the genes, biosynthetic pathways, resistance mechanisms and bioactivities of selected phosphonates, as well as charac- terization of novel enzymatic activities involved in their synthesis. The specific aims for the proposed funding period are: (1) characterization of the biosynthesis and bioactivity of phosphonothrixin and related molecules, (2) characterization of the biosynthesis and bioactivity of phosphonates produced by host-associated enterobac- teria, and (3) development of improved genome-mining tools for phosphonate discovery. Relevance This research has the potential to discover phosphonate natural products with useful bioactivities and interesting chemical features. Moreover, characterization of the genes, enzymes and biosynthetic pathways needed for production of these compounds is likely to reveal novel biochemistry that significantly expands our understanding of the chemical transformations catalyzed by microbes, while paving the way for creation of strains that overpro- duce useful molecules and their derivatives.