Discovery, Design, and Development of Phosphonic Acid Antibiotics

描述(申请人提供)：磷酸是一种有效的、但未被开发的生物活性化合物，在治疗人类疾病方面前景广阔。自然界中产生的磷酸盐种类繁多，其中许多具有有用的生物活性。重要的是，磷酸的生物靶标有很大的不同，使它们可以用于治疗各种健康状况。在我们最初的资助期内，我们表明，磷酸盐的生物合成在自然界中令人惊讶地普遍存在，还有大量未确定特征的天然产品等待表征。有了这些成果，我们现在已经准备好全面进入该项目的发现和开发阶段。在接下来的五年里，我们预计将描述大量 新型的膦酸类化合物。将确定它们的化学结构，它们的生物活性 对它们的生物合成途径进行了评估和阐明。我们将利用这些信息来开发高效、经济地产生最有用的候选菌株的菌株。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，解决了这些主题中的每一个。我们提出了四个相互交织的研究项目，以发现、设计和开发新的和已知的膦酸类抗生素。第一个项目涉及利用基因组学、微生物遗传学和分子生物学发现、测序和表征编码膦添加生物合成的基因簇。第二个项目的重点是对在当前供资期间发现的丰富的新化合物进行结构说明，以及对膦酸类抗生素的生物合成途径进行生化重建。第三个项目将侧重于与磷酸盐生物合成有关的特殊催化剂的结构生物学和酶学，以及可用于克服磷酸盐生物活性的各种抗性决定因素。第四个项目将使用尖端合成生物学方法来设计天然和设计的膦酸生物合成途径，以经济地生产具有医学和工业重要性的膦酸化合物。这四个项目中的每个项目都将得到一个分析核心资源的协助，该资源将提供现代质谱学和核磁共振仪器以及技术支助。 整个项目将设在伊利诺伊大学新的基因组生物学研究所，项目团队在那里拥有一个单独的、大型的连续实验室。

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. Importantly, the biological targets of phosphonic acids vary substantially, allowing them to be used for treating a variety of health conditions. In our initial funding period we showed that phosphonate biosynthesis is surprisingly common in nature and that a wealth of uncharacterized natural products await characterization. Armed with these results, we are now ready to move fully into the discovery and development phase of the project. In the next five years we expect to characterize a large number of novel phosphonate compounds. Their chemical structures will be determined, their bioactivity profiles assessed and their biosynthetic pathways elucidated. We will use this information to develop strains that efficiently and economically produce the most useful candidates. 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, sequencing and characterization of gene clusters encoding phosphonic add biosynthesis using genomics, microbial genetics and molecular biology. The second project is focused on structural elucidation of the wealth of new compounds that have been discovered in the current funding period and on the biochemical reconstruction of the biosynthetic pathways of phosphonic acid antibiotics. The third project will focus on structural biology and enzymology of unusual catalysts involved in phosphonate biosynthesis and the various resistance determinants that may be utilized to overcome the biological activities of phosphonates. The fourth project will employ cutting-edge synthetic biology approaches to engineer both natural and designed phosphonic acid biosynthetic pathways for economical production of medically and industrially important phosphonic acid compounds. Each of the four projects will be aided by an Analytical Core resource that will provide modern mass-spectrometry and nuclear magnetic resonance instrumentation and technical support. The entire project will be housed in the new Institute for Genomic Biology at the University of Illinois, where the program project team occupies a single, large contiguous, laboratory.