Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria

项目摘要：受人类微生物组启发的疗法的发展至少在一定程度上受到限制 由于我们缺乏对人类相关（HA-）细菌如何与人类宿主交流的了解， 影响病原体。人类微生物组测序研究显示， 细菌种群和人类健康。尽管存在这些相关性和将HA细菌与 尽管HA细菌在小鼠中的致病性，HA细菌如何特异性地影响哺乳动物生理学的机制细节仍然存在， 大部分未知。在其他环境中，已知细菌严重依赖低分子量 化合物（小分子或天然产物）与其他生物体相互作用。同样，我们预计， HA细菌可能使用小分子与其人类宿主和病原体相互作用。安装 有证据表明，尽管每个人体微生物组都由复杂的细菌组成， 在大多数个体中，数量少得多的物种非常普遍。虽然我们不知道 确切地说，HA细菌负责维持人类健康或引起疾病，我们假设 这些常见的HA细菌产生的小分子可能在 在这些过程中。这项建议的中心目的是筛选代谢物产生的最常见的 观察HA-细菌在高通量生物活性筛选中鉴定GPCR和SARS-CoV-2-活性小 分子及其产生生物合成基因簇（BGC）。GPCR是最大的 真核细胞跨膜受体。众所周知，它们在人类生物学中扮演着多种多样的重要角色 并且易于被小分子调节。基于GPCR在以下方面发挥如此广泛的作用这一事实， 将环境中的化学信息转化为真核细胞中的生物信号，我相信， HA细菌可能通过产生与GPCR相互作用的小分子来影响宿主生理学。 SARS-CoV-2病毒的出现代表了一场没有治疗药物的全球性大流行 治疗。本提案的两个目的将导致（1）鉴定，分离和结构阐明 HA细菌编码的代谢产物，与不同的GPCR相互作用或抑制SARS-CoV-2，（2） 这些代谢物的基因簇的表征，和（3）通过 殖民细菌这些研究将有助于阐明HA细菌如何形成的机制细节 人体健康据报道，人类微生物组影响复杂的病理生理过程， 从免疫系统的调节到大脑和中枢神经系统的发育。 HA细菌种群的变化与影响超过2亿美国人的疾病有关 包括肥胖、糖尿病、炎症性肠病、自闭症、肠易激综合征和肝硬化， 其他许多人.来源于HA-细菌的疗法在控制多种基本生物学特性方面具有潜在的实用性。 过程和人类疾病。

Project summary: The development of therapies inspired by the human microbiome is at least in part limited by our lack of understanding of how human associated (HA-) bacteria communicate with their human host and affect pathogens. Human microbiome sequencing studies show strong correlations between changes in bacterial populations and human health. Despite these correlations and the evidence linking HA-bacteria to disease in mice, the mechanistic details of how HA-bacteria specifically affect mammalian physiology remain largely unknown. In other environments, bacteria are known to rely heavily on low molecular weight compounds (small molecules or natural products) to interact with other organisms. Similarly, we expect that HA-bacteria are likely to use small molecules to interact with their human hosts and pathogens. Mounting evidence suggests that, although each human microbiome is composed of a complex collection of bacteria, a much smaller number of species is highly prevalent across the majority of individuals. While we don’t know exactly which HA-bacteria are responsible for maintaining human health or causing disease, we hypothesize that small molecules produced by these commonly encountered HA-bacteria are likely to play an important role in these processes. The central aim of this proposal is to screen metabolites produced by the most commonly observed HA-bacteria in high-throughput bioactivity screening to identify GPCR and SARS-CoV-2-active small molecules and their producing biosynthetic gene clusters (BGCs). GPCRs constitute the largest family of eukaryotic trans-membrane receptors. They are known to play diverse and profound roles in human biology and are prone to regulation by small molecules. Based on the fact that GPCRs play such an extensive role in transforming chemical information from the environment into biological signals in eukaryotic cells, I believe that HA-bacteria likely affect host physiology through the production of small molecules that interact with GPCRs. The emergence of the SARS-CoV-2 virus represents a worldwide pandemic with no therapeutic drug treatments. The two Aims of this proposal will result in (1) the identification, isolation, and structure elucidation of HA-bacteria-encoded metabolites that either interact with diverse GPCRs or inhibit SARS-CoV-2, (2) the characterization of the gene clusters for these metabolites, and (3) the validation of their production by colonizing bacteria. These studies will help to illuminate the mechanistic details of how HA-bacteria shape human health. The human microbiome is reported to influence complex pathophysiological processes ranging from the regulation of the immune system to the development of the brain and the central nervous system. Changes in HA-bacterial populations are associated with diseases that affect over 200 million Americans including obesity, diabetes, inflammatory bowel disease, autism, irritable bowel syndrome, and cirrhosis among many others. Therapies derived from HA-bacteria have potential utility in controlling diverse basic biological processes and human diseases.