The Program Project goals towards the discovery and characterization of novel phosphonates have benefited significantly from biochemical and structural biological characterization of the enzymes involved in the biosynthesis of these natural products. Additionally, detailed knowledge of the threedimensional structures of such enzymes in complex with their cognate substrates/inhibitors can aid in the engineering of these catalysts to yield derivative compounds with improved biological and/or pharmacokinetic properties. In this next cycle, we expand our research aims towards the biochemical characterization of gene clusters involved in the biosynthesis of the antibacterial plumbemycin and the antifungal rhizoctlcin. The enzymes from these clusters direct the production of two natural products consisting of a common warhead (the threonine synthase inhibitor (Z)-L-2-amino-5-phosphono-3- pentenoic acid (APPA)) but with different peptide-based delivery vehicles. We will carry out in vitro reconstitution of individual enzymes from each of these clusters and utilize this knowledge for the production of additional peptidic and non-peptidic derivatives of APPA that can target a range of additional pathogenic organisms. Concurrently, we also aim to continue our structure-function studies of several of the biosynthetic enzymes that have been characterized during the initial cycle. Lastly, we will also characterize the mechanisms of resistance that are utilized by the producing organisms and may limit the biological utility of several phosphonates.
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