Antimicrobials from Mammalian Microbiomes

描述（由申请人提供）：传染病是对人类总体健康和福祉的长期威胁。不幸的是，近年来新的抗微生物药物先导物的发现已经放缓，部分原因是缺乏能够有效对抗感染性生物体的新型化学实体。因此，迫切需要开发新的化合物来源，这些化合物可以被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，但未被开发的次级代谢产物库的药物先导发现潜力：哺乳动物细菌。与人类相似，其他哺乳动物的微生物组由数千种细菌组成，其中许多生物体具有产生次级代谢产物的能力。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组衍生的细菌能够产生独特的次级代谢产物的研究报告，也没有测试它们在生物活性铅产生过程中的应用。我们提出了一个探索性的R21研究计划，该计划将哺乳动物微生物组的综合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。我们提出的计划是建立在天然产物化学组和微生物生态实验室之间的协同合作。这将使我们能够测试核心假设，即哺乳动物的微生物组含有大量未开发的次级代谢产物产生细菌，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，以产生独特的哺乳动物微生物组文库，这些文库将被系统地筛选以识别生物活性命中。将根据以下内容选择命中的子集 基于化学、分类学和基因组数据集的组合，用于放大测试和生物活性次级代谢物纯化/表征。这项研究意义重大，因为它将为确保基于天然产物的生物活性先导物提供新的资源，我们将利用这些资源来帮助振兴抗菌药物发现管道。我们预计，哺乳动物微生物组将成为鉴定新型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。 公共卫生相关性：需要新的抗菌化合物来对抗耐药致病菌和真菌带来的日益增长的威胁。研究哺乳动物微生物组中的新型有机物质将有助于激活抗菌药物发现管道，这对现代药物发现和开发计划的成功至关重要。

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. PUBLIC HEALTH RELEVANCE: New antimicrobial compounds are needed to combat the growing threat posed by drug-resistant pathogenic bacteria and fungi. Investigating mammalian microbiomes for novel organic substances will help invigorate the antimicrobial drug discovery pipeline, which is critical to the success of modern drug discovery and development programs.