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）：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。重要的是，磷酸的生物学靶标有很大的变化，从而可以用于治疗各种健康状况。在我们的最初资助期间，我们表明磷酸盐生物合成在本质上是令人惊讶的常见，并且大量未表征的天然产品正在等待特征。通过这些结果，我们现在准备完全进入项目的发现和开发阶段。在接下来的五年中，我们期望大量 新型磷酸化合物。他们的化学结构将被确定，它们的生物活性谱 评估及其生物合成途径。我们将使用这些信息来开发有效，经济上产生最有用的候选者的菌株。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基因组学，微生物遗传学和分子生物学的磷酸化基因簇的发现，测序和表征。第二个项目的重点是阐明在当前资金期间发现的新化合物的财富以及磷酸抗生素的生物合成途径的生化重建。第三个项目将重点关注与磷酸化生物合成的异常催化剂的结构生物学和酶学，以及可以用来克服磷酸盐生物学活性的各种耐药性决定因素。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磷酸生物合成途径，以经济生产医学和工业上重要的磷酸化合物。四个项目中的每个项目都将得到分析核心资源的帮助，该资源将提供现代的质谱法和核磁共振仪器和技术支持。 整个项目将安置在伊利诺伊大学的新基因组生物学研究所中，该计划项目团队占据了一个大型连续实验室。