Chemical Biology Approaches to Investigate Cell-Signaling and Competition in Complex Bacterial Communities

细菌群落在其自然生态位中的复杂结构阻碍了我们对 物种间的相互作用决定了整个种群的构成。细菌扮演的关键角色 在人类健康中，通过执行必要的过程，如食物消化或通过侵入性 导致各种慢性和急性疾病的感染，突出了开发新方法的必要性 这将使我们能够研究复杂的细菌种群，例如人类微生物群。未能做到 因此，可能会阻碍社会微生物学领域的进一步发展，从而防止 开发利用细菌行为的新策略来提高数百万人的生活质量 世界各地的人们。该研究计划的长期目标是利用细菌传播 研究自然生态位中复杂细菌群落的途径。为此，在过去两年和 在半年的时间里，我们研究了多种细菌的群体感应(QS)回路。 基于不同活性分布的QS调节剂被开发出来。未来三年的目标是 扩展可用于QS调制的化学工具箱并利用开发的QS调制器来 探讨QS对复杂细菌群落总体种群组成的影响。这个 中心假设是QS，一种细胞-细胞信号机制，使细菌能够评估他们的 种群密度通过产生、分泌和检测信号分子，参与 种内和种间细菌交流，并在细菌中发挥重要作用 竞争，从而在塑造复杂社区的总体人口构成方面也是如此。其基本原理是 一旦QS在复杂细菌群落中的作用被确定，QS调节剂能够 确定了改变种群组成的一种创新方法，以利用细菌来改善 人类健康是可以发展的。以强有力的科学前提和初步成果为指导，包括 在该奖项的头两年半中获得的结果，这一假设将通过结合 传统遗传微生物学与化学生物学技术和结构生物学分析 基于多肽的探针，以揭示QS在复杂细菌群落中的作用。方法是 申请人认为，这是一种创新，因为它代表着与现状的实质性背离， 关注QS对物种间交流和竞争的影响，而不是QS的作用 电路在物种间的交流中发挥作用。拟议的研究具有重要意义，因为它是预期的 既要确定细菌传播在确定总体种群构成中所起的作用，又要 提供了一种新的策略来利用细菌行为来促进生产过程并减少 有害的表型最终改善全世界数百万人的整体生活质量。

The complex architectures of bacterial communities in their natural niches hinders our understanding of the interspecies interactions that shape the overall population composition. The critical role bacteria play in human health, either by carrying out essential processes such as food digestion or through invasive infections that cause diverse chronic and acute diseases, highlight the need to develop new approaches that will enable us to study complex bacterial populations, such as the human microbiome. Failing to do so, will likely hinder further advancement in the field of sociomicrobiology and consequently prevent the development of novel strategies to harness bacterial behaviors to improve the quality of life of millions of people worldwide. The long-term goal of the research program is to utilize bacterial communication pathways to study complex bacterial communities in their natural niches. To this end, in the past two and a half years, the quorum sensing (QS) circuits of a variety of bacterial species were studied and peptide- based QS modulators with diverse activity profiles were developed. The goals for the next three years are to expand the chemical toolbox available for QS modulation and utilize the developed QS modulators to probe the effects QS has on the overall population composition of complex bacterial communities. The central hypothesis is that QS, a cell-cell signaling mechanism that enables bacteria to assess their population density through the production, secretion and detection of signal molecules, is involved in both intra-species and inter-species bacterial communications, and has an important role in bacterial competition and thus in shaping the overall population composition of complex communities. The rationale is that once the role of QS in complex bacterial communities is determined and QS modulators capable of altering the population composition are identified, an innovative approach to harness bacteria to improve human health could be developed. Guided by strong scientific premise and preliminary results, including results obtained in the first two and a half years of this award, this hypothesis will be tested by combining traditional genetic microbiology along with chemical biology techniques and structural biology analysis of peptide-based probes to uncover the role of QS in complex bacterial communities. The approach is innovative, in the applicant's opinion, because it represents a substantial departure from the status quo by focusing on the effect QS has on inter-species communication and competition, rather than on the role QS circuits play in intra-species communication. The proposed research is significant because it is expected to both define the role bacterial communication play in determining the overall population composition, and provide a novel strategy to harness bacterial behavior to promote productive processes and attenuate harmful phenotypes to ultimately improve the overall quality of life of millions of people worldwide.