Discovery, Design, and Development of Phosphonic Acid Antibiotics

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希望。自然界中产生了各种各样的磷酸盐，其中许多具有有用的生物活性。重要的是，膦酸的生物学靶点变化很大，使它们能够用于治疗各种健康状况。在我们最初的资助时期，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等待表征。有了这些结果，我们现在准备完全进入项目的发现和开发阶段。在未来的五年里，我们预计将有大量的

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.