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，在过去三年中， 多年来，人们研究了各种细菌物种的群体感应(QS)回路，并以多肽为基础 具有不同活性分布的QS调节剂被开发出来。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。中环 假设是QS，一种细胞-细胞信号机制，使细菌能够评估其种群 密度通过信号分子的产生、分泌和检测，参与体内 物种和物种间的细菌通讯，并在细菌竞争中发挥重要作用 因此在塑造复杂社区的总体人口构成方面也是如此。理由是，一旦 确定了qs在复杂细菌群落中的作用，并且qs调节剂能够改变 确定了种群组成，这是一种利用细菌改善人类健康的创新方法 可能会被开发出来。在强有力的科学前提和初步结果的指导下，这一假说将是 通过结合传统的遗传微生物学和化学生物学技术进行测试， 多肽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，这种方法是创新的，因为它 通过关注QS对物种间的影响，代表了对现状的实质性偏离 交流和竞争，而不是QS回路在物种内交流中所起的作用。 这项拟议的研究具有重要意义，因为它有望定义细菌传播的作用 在确定总体种群组成方面发挥作用，并提供了一种新的策略来治理细菌 促进生产过程和减少有害表型的行为，最终改善 全球数百万人的总体生活质量。

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.