Discovery, Design, and Development of Phosphonic Acid Antibiotics

膦酸抗生素的发现、设计和开发

• 批准号: 8457035
• 负责人: WILLIAM W METCALF
• 金额: $ 151.57万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457035
• 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

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）：膦酸是一种有效但尚未开发的生物活性化合物，在治疗人类疾病方面具有很大的前景。在自然界中产生了各种各样的膦酸酯，其中许多具有有用的生物活性。重要的是，膦酸的生物靶点差异很大，使它们能够用于治疗各种健康状况。在我们最初的资助期间，我们发现膦酸盐生物合成在自然界中惊人地普遍，并且大量未表征的天然产物等待表征。有了这些结果，我们现在准备全面进入项目的发现和开发阶段。在未来的五年里，我们希望能够描述大量的 新的膦酸酯化合物。它们的化学结构将被确定，它们的生物活性概况 评估并阐明其生物合成途径。我们将利用这些信息来开发菌株，以有效和经济地生产最有用的候选物。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、测序和表征编码膦酸酯生物合成的基因簇。第二个项目的重点是对本资助期内发现的大量新化合物进行结构解析，以及对膦酸类抗生素的生物合成途径进行生物化学重建。第三个项目将侧重于结构生物学和酶的不寻常的催化剂参与膦酸酯的生物合成和各种抗性决定因素，可用于克服膦酸酯的生物活性。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一个分析核心资源的帮助，该资源将提供现代质谱和核磁共振仪器和技术支持。 整个项目将被安置在伊利诺伊大学新的基因组生物学研究所，在那里项目团队占据了一个单一的，大型的连续实验室。