Discovery, Design, and Development of Phosphonic Acid Antibiotics

膦酸抗生素的发现、设计和开发

• 批准号: 8053862
• 负责人: WILLIAM W METCALF
• 金额: $ 135.91万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2012-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053862
• 关键词: Discovery; Design; Development; Phosphonic; Acid

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.

膦酸是一组有效但尚未充分开发的生物活性化合物，在治疗人类疾病方面具有巨大的前景。自然界中产生了多种膦酸盐，其中许多具有有用的生物活性。其中包括磷霉素（一种治疗妊娠期急性膀胱炎的常见药物）和 FR900098（一种治疗疟疾的新型疗法（和治愈方法！））。其他包括膦丝菌三肽 (PIT) 是一种广泛使用的除草剂，K-26 是一种在治疗高血压方面很有前景的化合物。膦酸盐抑制剂的靶点差异很大，允许它们用于治疗多种病症，但尽管它们具有实用性，但令人惊讶的是，人们对这些天然产物的生物合成知之甚少。正如该提案中所述，我们相信有充分的理由相信（i）其他天然膦酸产品仍有待发现（包括具有新治疗靶点的产品），（ii）大量新的生物化学和次级代谢将被开发出来。期间发现 膦酸生物合成途径的表征，（iii）可以修改和改进目前已知的化合物，以及（iv）可以开发更经济的生产方法。拟议的计划项目通过涉及微生物学、生物化学、化学、代谢工程和结构生物学的多学科研究计划来解决这些主题。我们提出了四个相互交织的研究项目来发现、设计和开发新型和已知的膦酸抗生素。 第一个项目涉及利用微生物遗传学和分子生物学发现、鉴定和表征编码膦酸生物合成的基因簇。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，包括参与这些含 C-P 键化合物合成的几个完全前所未有的酶促反应。第三个项目 涉及天然和设计的膦酸生物合成途径的生物工程，以允许膦酸抗生素的过量生产。第四个项目的重点是开发和使用质谱法来检测和量化膦酸并表征其合成中涉及的生化反应。该项目将设在伊利诺伊大学新的基因组生物学研究所，项目团队将在那里占据一个大型连续实验室。