Antimicrobials from Mammalian Microbiomes

描述(申请人提供)：传染病是对人类一般健康和福利的长期威胁。不幸的是，近年来发现新的抗微生物药物的速度有所放缓，部分原因是缺乏能够有效对抗感染性生物的新的化学实体。因此，迫切需要开发新的化合物来源，这些化合物可以用来测试以鉴定新的生物活性药效团。在这个项目中，我们建议调查一个巨大的、但未被充分开发的次生代谢物储藏库的药物先导发现潜力：来自哺乳动物的细菌。与人类类似，其他哺乳动物的微生物群由数千种细菌组成，其中许多生物具有产生次生代谢物的能力。尽管有这种令人难以置信的潜力，但几乎没有关于哪些微生物群衍生的细菌能够产生独特的次生代谢物的研究报告，也没有对它们在生物活性铅产生过程中的应用进行测试。我们提出了一个探索性的R21研究计划，将哺乳动物微生物群的全面培养与化学和分子方法学方法相结合，以批判性地评估这些微生物组合，以发现新的抗菌天然产物。我们建议的计划是建立在天然产品化学小组和微生物生态实验室之间的协同合作基础上的。这将使我们能够检验哺乳动物的微生物群包含大量尚未开发的次生代谢物产生细菌的中心假设，并确定这些化合物抑制细菌和真菌病原体生长的能力。我们将测试一系列培养技术，以生产独特的哺乳动物微生物文库，并将对其进行系统筛选，以识别具有生物活性的化合物。将根据以下条件选择命中的子集 结合化学、分类学和基因组数据集进行放大测试和生物活性次生代谢物纯化/表征。这项研究具有重要意义，因为它将为确保基于天然产品的生物活性线索提供新的资源，我们将利用这些线索来帮助振兴抗菌药物发现管道。我们预计，哺乳动物微生物群将成为识别新的有机物质的宝贵资源，这些物质是现代药物开发计划成功的关键。

DESCRIPTION (provided by applicant): Infectious disease represents a perennial threat to the general health and welfare of humankind. Unfortunately, the discovery of new antimicrobial drug leads has slowed in recent years due in part to a lack of novel chemical entities capable of effectively combating infectious organisms. Consequently, there is a critical need for developing new sources of compounds that can be tested to identifying novel bioactive pharmacophores. In this project, we propose to investigate the drug-lead discovery potential of a vast, but under-explored reservoir of secondary metabolites: bacteria from mammals. Similar to humans, the microbiomes of other mammals are composed of thousands of bacterial species and many of these organisms have the capacity to generate secondary metabolites. Despite this incredible potential, virtually no research effort has been reported regarding which microbiome-derived bacteria are capable of producing unique secondary metabolites, nor have their applications to the bioactive lead generation process been tested. We propose an exploratory R21 research program that combines the comprehensive cultivation of mammalian microbiomes with chemical and molecular methodological approaches to critically evaluate these microbial assemblages for the discovery of new antimicrobial natural products. Our proposed program is founded on a synergistic collaboration between a natural products chemistry group and microbial ecology laboratory. This will enable us to test the central hypothesis that the microbiomes of mammals contain an untapped wealth of secondary-metabolite-producing bacteria and determine the capacity for these compounds to inhibit the growth of bacterial and fungal pathogens. We will test a range of cultivation techniques to produce unique mammalian microbiome libraries that will be systematically screened to identify bioactive hits. A subset of hits will be selected based on a combination of chemical, taxonomic, and genomic datasets for scale-up testing and bioactive secondary metabolite purification/characterization. This research is significant because it will provide a new resource for securing natural-product-based bioactive leads, which we will use to help invigorate the antimicrobial drug discovery pipeline. We expect that mammalian microbiomes will become a valuable resource for identifying novel organic substances that are key to the success of modern drug development programs.