EFRI-MIKS: Deciphering and Controlling the Signaling Processes in Bacterial Multicellular Systems and Bacteria-Host Interactions

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1137186 RenIntellectual Merit:Bacteria are well known to obtain intrinsic tolerance to antibiotics and disinfectants by forming surfaceattachedsessile colonies embedded in an extracellular matrix, known as biofilms, and by formingmetabolically inactive cells, known as persister cells. Such intrinsic tolerance also facilitates thedevelopment of multidrug resistance through acquired mechanisms, presenting a great challenge tomicrobial control.Despite the well recognized significance, research on biofilms and persister cells is still in its infancy.Distribution of persisters in biofilms and the effects of environmental/host factors and cell-cell signalingon such distribution and biofilm-associated stress tolerance are unknown, mostly due to the heterogeneityin biofilm structure, spatial and temporal variation in gene expression, and redundancy in persister andbiofilm genes. The objective of this EFRI project is therefore to understand and manipulate themulticellular and inter-kingdom signaling processes in such complex systems by addressing these keychallenges using well integrated multidisciplinary approaches.Based on recent successes in surface engineering, patterned biofilm formation, systems biology andmolecular simulation, this research team will conduct the first-of-its-kind research to: (1) systematicallycharacterize persister formation during biofilm development, (2) identify the roles of key genes andsignaling processes in persister formation, (3) develop an unprecedented computational capability toaccurately predict signaling factor translocation through the extracellular matrix of the biofilms, and (4)synthesize and characterize functional nanoparticles for controlled release of signaling modulators toeliminate persister cells. A number of important questions will be answered for the first time. Thesediscoveries will have a transformative impact in designing more effective knowledge-based strategies forthe manipulation and control of bacterial multicellular behaviors and bacteria-host interactions.Broader Impacts:In addition to fundamental understanding of biofilm development and persister formation, the findingsfrom this study will also improve the general knowledge of bacterial physiology with the potential to shiftthe paradigm of microbial control. Furthermore, the results of this research as pertains to deleteriousbiofilms of pathogenic and corrosive bacteria can be extended to the development of better biofilmsystems of environmentally friendly bacteria, which have broad applications in bioremediation of toxicchemicals and economical production of renewable biofuels. Due to the broad spectrum of problems andopportunities associated with persister cells and biofilms, the proposed work will have significant impactson basic science, economy, biosecurity and health care.Beyond any technical achievements, this project will also play an important role in transforming collegeengineering education. Unlike traditional projects that focus on relatively narrow topics, this projecttargets multicellular and inter-kingdom signaling, a highly interdisciplinary area. The advanced topicsassociated with this research will provide invaluable materials to teach modern biotechnology, molecularsimulation, synthetic biology and bioinformatics, providing the students with crucial knowledge and skillsto address the scientific, engineering and societal challenges. This research will also create excitingoutreach opportunities and bring talented young people, especially underrepresented groups, into scienceand engineering careers.