BIOSYNTHETIC ENZYMES OF PHOSPHONIC ACID ANTIBIOTICS

近年来出现了大量的多重耐药菌株的报道， 造成对所有市售抗生素免疫的威胁。为了防止 潜在的传染病流行爆发，高度期望对抗生素研究的重新关注， 包括寻找具有替代细胞靶点的新天然产物， 细胞毒性和抗性的机制，以及对其生物合成途径的理解。相对 关于生物合成途径尚未探索的是膦酸盐抗生素，尽管它们在生物合成中有潜在的用途。 抗菌、抗病毒和抗寄生虫疗法。此外，它们还广泛用于农业， 除草剂和杀虫剂。该项目旨在从生物化学上表征 这些化合物中的几种包括双丙氨膦（膦丝菌素三肽）和A53868， 序列信息可从该程序项目内的合作者获得。蛋白质将在 E. coli或S.将通过化学方法合成并纯化青丹及其推定的底物。除了 阐明生物合成途径，一组特殊酶的机制也将被阐明。 研究了该项目还将增加遗传研究发现的天然膦酸盐， 合成的偏向文库将集中于天然存在的膦酸酯的类似物。最初的图书馆将 重点关注K-26和A53868

Numerous reports of multi-drug resistant bacterial strains have appeared in recent years, with several strains posing the threat of becoming immune against all commercially available antibiotics. In order to prevent potential 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 the mechanisms of cytotoxicity and resistance, and the understanding of their biosynthetic pathways. Relatively unexplored with respect to biosynthetic pathways are phosphonate antibiotics, despite their potential use in antibacterial, antiviral, and antiparasitic therapies. Moreover, they are used extensively in agriculture as herbicides and pesticides. This project aims to biochemically characterize the biosynthetic pathways of several of these compounds including bialaphos (phosphinothricin tripeptide) and A53868 using the gene sequence information available from collaborators within this program project. Proteins will be expressed in E. coli or S. lividans and purified and their putative substrates will be chemically synthesized. In addition to elucidating the biosynthetic pathway, the mechanism of a select group of unusual enzymes will also be investigated. This project will also augment the natural phosphonates discovered by genetic studies with synthetic biased libraries that will focus on analogs of natural occurring phosphonates. The initial libraries will focus on K-26 and A53868.