Discovery, Design, and Development of Phosphonic Acid Antibiotics

膦酸代表了一种有效的，但尚未开发的， 一组在人类疾病治疗中具有巨大前景的生物活性化合物。各种各样的 膦酸盐在自然界中产生，并且许多具有有用的生物活性。其中包括 磷霉素，妊娠期间急性膀胱炎的常用治疗，和FR 900098，一种新的治疗方法 (and治愈！）治疗疟疾其他包括广泛使用的除草剂膦丝菌素肽（PIT）和K- 26，一种在治疗高血压方面前景广阔的化合物。膦酸盐的靶点 抑制剂变化很大，允许它们用于治疗各种各样的病症，然而尽管它们具有良好的抗肿瘤活性， 尽管这些天然产物的用途有限，但令人惊讶的是，关于这些天然产物的生物合成知之甚少。正如本文所述， 建议，我们认为有充分的理由相信，（i）额外的天然膦酸 产品仍有待发现（包括具有新的治疗靶点的产品），（ii）大量的 新的生化和次生代谢将发现在表征膦酸 酸生物合成途径，（iii）目前已知的化合物可以被修饰和改进，以及（iv） 可以开发出更经济的生产方法。拟议方案项目 通过涉及微生物学的多学科研究计划解决这些主题中的每一个， 生物化学、化学、代谢工程和结构生物学。我们提出四个相互交织的 研究项目，发现，设计和开发新的和已知的膦酸抗生素。的 第一个项目涉及发现、鉴定和表征编码膦酸的基因簇 利用微生物遗传学和分子生物学的方法进行酸的生物合成。第二个项目涉及 这些生物合成途径的化学和生物化学表征，包括几个完全 在这些含C-P键的化合物的合成中涉及前所未有的酶促反应。 第三个项目涉及生物工程的天然和设计的膦酸生物合成 途径，以允许过量生产膦酸抗生素。第四个项目的重点是 质谱法的开发和使用，以检测和定量膦酸， 描述其合成中涉及的生化反应。该项目将在新的 伊利诺伊大学基因组生物学研究所，该项目的项目小组将占据一个 一个大型的连续实验室

Phosphonic acids represent a potent, yet underexploited, group of bioactive compounds with great promise in the treatment of human disease. A wide variety of phosphonates are produced in nature and many have useful bioactive properties. Among these are fosfomycin, a common treatment for acute cystitis during pregnancy, and FR900098, a novel treatment (and cure!) for malaria. Others include phosphinothricintripeptide (PIT), a widely used herbicide, and K- 26, a compound with great promise in the treatment of high blood pressure. The targets of phosphonate inhibitors vary widely, allowing their use in the treatment of a wide variety of conditions, yet despite their utility, surprisingly little is known regarding the biosynthesis of these natural products. As outlined in this proposal, we believe there is ample reason to believe that (i) additional natural phosphonic acid products remain to be discovered (including ones with novel therapeutic targets), (ii) that a wealth of novel biochemistry and secondary metabolism will be discovered during characterization of phosphonic acid biosynthetic pathways, (iii) that currently known compounds can be modified and improved and (iv) that more economical methods for their production can be developed. The proposed Program Project addresses each of these topics via a multidisciplinary research program involving microbiology, biochemistry, chemistry, metabolic engineering and structural biology. We propose four intertwined research projects to discover, design and develop novel and known phosphonic acid antibiotics. The first project involves discovery, identification and characterization of gene clusters encoding phosphonic acid biosynthesis using microbial genetics and molecular biology. The second project involves the chemical and biochemical characterization of these biosynthetic pathways, including several entirely unprecedented enzymatic reactions involved in synthesis of these C-P bond-containing compounds. The third project involves bioengineering of natural and designed phosphonic acid biosynthetic pathways to allow overproduction of phosphonic acid antibiotics. The fourth project is focused on the development and use of mass-spectrometry to detect and quantify phosphonic acids and to characterize the biochemical reactions involved in their synthesis. The project will be housed in the new Institute for Genomic Biology at the University of Illinois, where the program project team will occupy a single, large contiguous laboratory.