PAPM EAGER: Identifying Small Molecule Inhibitors that Manipulate

EIGHER奖将探索研究复杂微生物群落(微生物群)内发生的化学反应的新战略：开发类药物小分子，选择性地抑制在这些栖息地发生的特定微生物代谢活动。生活在微生物群中的微生物进行化学转化(新陈代谢)，使它们能够生长和生存，调节与其他生物的相互作用，并影响周围环境的健康。尽管这些化学过程很重要，但它们如何影响微生物群稳定性和功能的细节尚不清楚，部分原因是群落中的生物体不能用遗传学来操纵。获得扰乱个体反应的小分子将改变微生物组研究，使不同学科的科学家能够在复杂的群落环境中操纵特定的微生物活动，并观察对群落和周围环境和有机体的后果。这些工具将普遍适用于多种类型的微生物群落，它们可以在许多方面造福社会：改变人类微生物群以预防或治疗疾病；调整植物微生物群以提高作物生产力或保护其免受病原体侵袭；调节土壤微生物群以防止产生温室气体的代谢活动。最后，该项目将为年轻科学家提供一个独特的跨学科培训机会，使他们接触到化学生物学和微生物学的研究。微生物组研究的一个主要障碍是阐明单个微生物代谢活动如何塑造这些组合并影响它们与其他生物体的相互作用。该项目的长期目标是开发一套小分子抑制剂，可以被微生物组研究界用作在体内操纵特定微生物功能的变革性工具。提出的识别初始铅抑制物的方法依赖于基于差异生长的分析方法的体内高通量筛选。这一策略应该会迅速揭示抑制细菌利用特定生长底物的分子。重要的是，这种筛选模式要求抑制剂从一开始就在一组不同的靶标生物体的背景下有效。纳入这一严格的标准将确保HITS可以迅速发展为创新的工具化合物，选择性地改变体内特定的微生物活动，提供有关它们在塑造群落、微生物-微生物相互作用和宿主生物学方面的作用的信息。这项急切的提案将侧重于执行最初的高通量筛选，以发现厌氧细菌胆碱利用的抑制剂，以及开发针对更多微生物代谢活动的基于生长的分析方法。

The EAGER award will explore a new strategy for studying the chemical reactions taking place within complex microbial communities (microbiomes): the development of drug-like small molecules that will selectively inhibit specific microbial metabolic activities occurring in these habitats. Microorganisms living in microbiomes carry out chemical transformations (metabolism) that enable their growth and survival, mediate interactions with other organisms, and influence the health of surrounding environments. Despite the importance of these chemical processes, the details of how they affect microbiome stability and function are not yet understood, in part because organisms in communities cannot be manipulated using genetics. Access to small molecules that perturb individual reactions would transform microbiome research by enabling scientists across different disciplines to manipulate specific microbial activities in a complex community setting and observe the consequences for the community and surrounding environments and organisms. These tools would be generally applicable across multiple types of microbial communities, and they could benefit society in numerous ways: altering the human microbiome to prevent or treat disease; adjusting plant microbiomes to provide improved crop productivity or protection from pathogens; and modulating soil microbiomes to prevent metabolic activities that generate greenhouse gases. Finally, this project will offer a unique, interdisciplinary training opportunity for young scientists by exposing them to research at the interface of chemical biology and microbiology.A major obstacle in microbiome research is elucidating how individual microbial metabolic activities shape these assemblages and affect their interactions with other organisms. The long-term goal of this project is to develop a set of small molecule inhibitors that may be used by the microbiome research community as transformative tools for manipulating specific microbial functions in vivo. The proposed approach for identifying initial lead inhibitors relies on in vivo high-throughput screens using differential growth-based assays. This strategy should rapidly reveal molecules that inhibit bacterial utilization of specific growth substrates. Importantly, this screening paradigm requires that inhibitors are efficacious in the context of a diverse set of target organisms from the outset. Incorporating this stringent criterion will ensure hits can be quickly progressed to innovative tool compounds that selectively alter specific microbial activities in vivo, providing information about their roles in shaping communities, microbe-microbe interactions, and host biology. This EAGER proposal will focus on the execution of an initial high-throughput screen to uncover inhibitors of anaerobic bacterial choline utilization, as well as the development of growth-based assays targeting additional microbial metabolic activities.