Discovery, Design, and Development of Phosphonic Acid Antibiotics

膦酸抗生素的发现、设计和开发

• 批准号: 7619572
• 负责人: WILLIAM W METCALF
• 金额: $ 136.61万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619572
• 关键词: Discovery; Design; Development; Phosphonic; Acid

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：磷酸代表了一种有效但无流行的生物活性化合物，对人类疾病的治疗有很大的希望。自然界中产生了多种磷酸盐，许多磷具有有用的生物活性特性。其中包括Fosfomycin，是怀孕期间急性膀胱炎的常见治疗方法，而FR900098是疟疾的新型治疗方法（和治愈！）。其他包括磷脂毒素（PIT），一种广泛使用的除草剂和K-26，这是一种在治疗高血压方面具有很大希望的化合物。膦酸酯抑制剂的靶标有很大的变化，可以在治疗多种疾病的治疗中使用，尽管它们有用，但对于这些天然产物的生物合成而言，鲜为人知。正如该提议中概述的那样，我们认为有充分的理由相信（i）（i）（i）额外的天然磷酸产品仍有待发现（包括具有新型治疗靶标的），（ii），（ii），在磷酸生物合成过程中的表征，（iiii）（iiii）（iii iii），将会发现大量新型的生物化学和次要代谢，（III）将发现更多的生物化学和次要代谢。可以开发生产。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，以发现，设计和开发新颖和已知的磷酸抗生素。第一个项目涉及使用微生物遗传学和分子生物学编码磷酸生物合成的基因簇的发现，鉴定和表征。第二个项目涉及这些生物合成途径的化学和生化表征，包括几种与这些含C-P键合成化合物合成的完全前所未有的酶促反应。第三个项目涉及天然和设计的磷酸生物合成途径的生物工程，以使磷酸抗生素过量生产。第四个项目的重点是开发和使用质谱法来检测和量化磷酸，并表征其合成所涉及的生化反应。该项目将安置在伊利诺伊大学的新基因组生物学研究所中，该计划项目团队将占据一个大型连续实验室。