CHEMICAL BIOLOGY APPROACHES TO INVESTIGATE CELL-SIGNALING AND COMPETITION IN COMPLEX BACTERIAL COMMUNITIES

The complex architectures of bacterial communities in their natural niches hinders our understanding ofthe interspecies interactions that shape the overall population composition. The critical role bacteria playin human health, either by carrying out essential processes such as food digestion or through invasiveinfections that cause diverse chronic and acute diseases, highlight the need to develop new approachesthat will enable us to study complex bacterial populations, such as the human microbiome. Failing to doso, will likely hinder further advancement in the field of sociomicrobiology and consequently prevent thedevelopment of novel strategies to harness bacterial behaviors to improve the quality of life of millions ofpeople worldwide. The long-term goal of the research program is to utilize bacterial communicationpathways to study complex bacterial communities in their natural niches. To this end, in the past threeyears, the quorum sensing (QS) circuits of a variety of bacterial species were studied and peptide-basedQS modulators with diverse activity profiles were developed. The goals for the next five years are to expandthe chemical toolbox available for QS modulation and utilize the developed QS modulators to probe theeffects QS has on the overall population composition of complex bacterial communities. The centralhypothesis is that QS, a cell-cell signaling mechanism that enables bacteria to assess their populationdensity 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 competitionand thus in shaping the overall population composition of complex communities. The rationale is that oncethe role of QS in complex bacterial communities is determined and QS modulators capable of altering thepopulation composition are identified, an innovative approach to harness bacteria to improve human healthcould be developed. Guided by strong scientific premise and preliminary results, this hypothesis will betested 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 QSin complex bacterial communities. The approach is innovative, in the applicant?s opinion, because itrepresents a substantial departure from the status quo by focusing on the effect QS has on inter-speciescommunication 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 communicationplay in determining the overall population composition, and provide a novel strategy to harness bacterialbehavior to promote productive processes and attenuate harmful phenotypes to ultimately improve theoverall quality of life of millions of people worldwide.