Numerous reports of multi-drug resistant bacterial strains have appeared in recent years, with several strainsposing the threat of becoming immune against all commercially available antibiotics. In order to preventpotential epidemic outbreaks of infectious diseases, a renewed focus on antibiotic research is highly desired,including the search for new natural products with alternative cellular targets, the investigation of themechanisms of cytotoxicity and resistance, and the understanding of their biosynthetic pathways. Relativelyunexplored with respect to biosynthetic pathways are phosphonate antibiotics, despite their potential use inantibacterial, antiviral, and antiparasitic therapies. Moreover, they are used extensively in agriculture asherbicides and pesticides. This project aims to biochemically characterize the biosynthetic pathways ofseveral of these compounds including bialaphos (phosphinothricin tripeptide) and A53868 using the genesequence information available from collaborators within this program project. Proteins will be expressed inE. coli or S. lividans and purified and their putative substrates will be chemically synthesized. In addition toelucidating the biosynthetic pathway, the mechanism of a select group of unusual enzymes will also beinvestigated. This project will also augment the natural phosphonates discovered by genetic studies withsynthetic biased libraries that will focus on analogs of natural occurring phosphonates. The initial libraries willfocus on K-26 and A53868.
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