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

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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.