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组成。细菌扮演的关键角色 在人类健康中，无论是通过进行食物消化等基本过程，还是通过侵入性的 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，例如人类微生物组。未能做到 因此，这可能会阻碍社会微生物学领域的进一步发展， 开发利用细菌行为的新策略，以改善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通讯 研究自然生态位中复杂细菌群落的途径。为此，在过去的三年里， 多年来，研究了各种细菌物种的群体感应（QS）回路，并基于肽 开发了具有不同活性特征的QS调节剂。未来五年的目标是扩大 可用于QS调制的化学工具箱，并利用开发的QS调制器来探测 QS对复杂细菌群落的总体种群组成的影响。中央 假设是QS，一种使细菌能够评估其种群的细胞-细胞信号传导机制， 密度通过生产，分泌和信号分子的检测，涉及两个内， 种和种间细菌通信，并在细菌竞争中发挥重要作用 从而影响复杂社区的总体人口构成。理由是，一旦 确定了QS在复杂细菌群落中的作用，并确定了能够改变细菌群落的QS调节剂。 确定了细菌的种群组成，这是一种利用细菌改善人类健康的创新方法 可以开发。在强有力的科学前提和初步结果的指导下，这一假设将被 通过将传统的遗传微生物学沿着化学生物学技术相结合进行测试， 基于肽的探针的计算建模和结构生物学分析，以揭示QS的作用 在复杂的细菌群落中。申请人认为，这一方法是创新的，因为它 通过关注QS对物种间的影响， 通信和竞争，而不是QS电路在物种内通信中发挥的作用。 这项拟议中的研究意义重大，因为它有望同时定义细菌传播的作用， 在决定总体种群组成方面发挥作用，并提供了一种新的策略来利用细菌 行为，以促进生产过程和减弱有害的表型，以最终改善 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 three 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 five 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, this hypothesis will be tested by combining traditional genetic microbiology along with chemical biology techniques, computational modeling 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.