Discovery, Design, and Development of Phosphonic Acid Antibiotics

膦酸抗生素的发现、设计和开发

基本信息

批准号：
8634110
负责人：
WILLIAM W METCALF
金额：
$ 157.06万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-10 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634110
关键词：
Acids Actinobacteria class Address Anabolism Antibiotic Resistance Antibiotics Bacillus (bacterium)Biochemical Biochemistry Bioinformatics Biological Biological Assay Biological Factors Biology Chemical Structure Chemicals Chemistry Coculture Techniques Corynebacterium glutamicum Data Development Dose Engineering Enzymatic Biochemistry Enzymes Exposure to Funding Gene Cluster Genes Genetic Genomics Goals Gram-Positive Bacteria Growth Health Herbicides Housing Human Illinois Individual Industrial fungicide Institutes Interdisciplinary Study Knowledge Laboratories Lesion Mass Spectrum Analysis Metabolic Pathway Methods Microbial Genetics Microbiology Molecular Molecular Biology Molecular Genetics Nature Nuclear Magnetic Resonance Pathway interactions Pesticides Pharmacologic Substance Phase Phosphonic Acids Phosphorus Phylogenetic Analysis Production Property Proteobacteria Pseudomonas aeruginosa Regulator Genes Research Research Project Grants Resistance Resources Series Source Staging Streptomyces System Universities antimicrobial arm catalyst cost design feeding genome sequencing human disease improved instrumentation metabolic engineering microbial microorganism mutant novel pathogen phosphonate programs reconstruction research study screening small molecule structural biology synthetic biology

项目摘要

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.

描述（由申请人提供）：膦酸代表了一组有效但尚未充分利用的生物活性化合物，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。重要的是，膦酸的生物靶标差异很大，使得它们可用于治疗各种健康状况。在我们最初的资助期间，我们表明膦酸盐生物合成在自然界中非常普遍，并且大量未表征的天然产物有待表征。有了这些结果，我们现在已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膦酸酯化合物。它们的化学结构和生物活性特征将被确定评估并阐明了它们的生物合成途径。我们将利用这些信息来开发菌株，以高效、经济地产生最有用的候选者。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基因组学、微生物遗传学和分子生物学对编码膦酸生物合成的基因簇进行发现、测序和表征。第二个项目的重点是对当前资助期间发现的大量新化合物进行结构阐明，以及膦酸抗生素生物合成途径的生化重建。第三个项目将重点关注膦酸盐生物合成中涉及的不寻常催化剂的结构生物学和酶学以及可用于克服膦酸盐生物活性的各种抗性决定因素。第四个项目将采用尖端的合成生物学方法来设计天然和设计的膦酸生物合成途径，以经济地生产医学和工业上重要的膦酸化合物。这四个项目中的每一个都将得到分析核心资源的协助，该资源将提供现代质谱和核磁共振仪器和技术支持。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大型连续实验室。