Chemical Biology of Mircobial Interspecies Signaling

描述（由申请人提供）：小分子天然产物，主要是微生物来源，已被广泛用作治疗剂数十年。大多数识别和表征此类化合物的研究要么是通过寻找抑制微生物生长的活性（抗生素），要么仅仅是通过微生物产物的化学鉴定，而没有任何关于其生物学功能的明确知识。近年来，我们已经开始认识到，许多微生物产品作为各种微生物感知的信号，作为它们适应环境的一部分。基于这种对天然产物作用的生态学观点，我们提出了我们的中心假设：细菌合成并分泌大量小信号分子，这些小信号分子影响占据相同栖息地的其他微生物的生理学。虽然这是推动拟议研究的一般假设，但我们提出的实验路线也是以发现为导向的：我们的目标是发现新的小分子，这些小分子可以介导微生物世界中多种物种间的相互作用。期望通过识别和表征这些分子，并研究它们的生物合成途径和生物功能，我们将产生一系列潜在的先导化合物。这些最终可以被开发为治疗剂，或者作为抗生素来治疗细菌感染，或者如目前临床使用的其他几种天然产品所证明的那样，以减轻其他痛苦。为了解决由细菌合成的信号化合物的问题，将导致发现许多这样的分子，我们已经设计了方法，融合了微生物生态学，生理学和遗传学的学科，酶学，生物信息学和小分子化学。在这种多学科的方式，我们将承担三个具体目标：（1）寻找新的微生物信号分子，（2）基因组挖掘代谢物刺激，和（3）新的小分子的表征：生物合成和生物活性。与公共卫生的相关性：抗生素作为治疗药物的发展是现代医学的关键成就之一。不幸的是，抗生素耐药性细菌的出现降低了现有抗生素的有效性。这项研究旨在发现新的抗生素和其他具有治疗潜力的药物。

DESCRIPTION (provided by applicant): Small molecule natural products, primarily of microbial origin, have been extensively used as therapeutic agents for decades. Most searches to identify and characterize such compounds have been dominated either by efforts that seek activities that inhibit microbial growth (antibiotics) or simply by the chemical identification of microbial products without any defined knowledge of their biological function. In recent years, we have begun to recognize that many microbial products serve as signals sensed by diverse microbes as part of the way they adapt to their environment. Based on this ecological perspective of the role of natural products we have developed our central hypothesis: Bacteria synthesize and secrete a large number of small signaling molecules that affect the physiology of other microbes that occupy the same habitat. While this is the general hypothesis driving the proposed research, the lines of experimentation we propose are also discovery-driven: we aim to discover new small molecules that mediate diverse interspecies interactions in the microbial world. The expectation is that by identifying and characterizing such molecules, and studying their biosynthetic pathways and biological functions, we will generate a collection of potential lead compounds. These could eventually be developed as therapeutic agents, either as antibiotics to treat bacterial infections or, as several other natural products currently in clinical use demonstrate, to alleviate other afflictions. To address the question of signaling compounds synthesized by bacteria in a way that will lead to the discovery of many such molecules we have devised approaches that meld the disciplines of microbial ecology, physiology, and genetics, with enzymology, bioinformatics, and small molecule chemistry. In this multidisciplinary manner we will undertake three specific aims: (1) Prospecting for novel microbial signaling molecules, (2) Genome mining by metabolite stimulation, and (3) Characterization of new small molecules: biosynthesis and biological activity. Relevance to public health: The development of antibiotics as therapeutics is one of the key accomplishments of modern medicine. Unfortunately, the appearance of antibiotic resistant bacteria has diminished the effectiveness of existing antiobiotics. The proposed research aims at discovering new antibiotics and other agents with therapeutic potential.