Therapeutic and Catalytic Applications of Electroactive Bacteria

Abstract Electroactive bacteria couple changes in the extracellular reduction-oxidation (redox) environment to their central carbon metabolism through extracellular electron transfer (EET). Several electroactive commensals and pathogens have been isolated from the human gut, oral cavity, and other locations, but their influence on host biology has not been examined. Accordingly, the overall goal of the proposed work is to uncover the fundamental role that EET plays in human health and to exploit this understanding to develop new therapeutics and biological catalysts. Building off our previous efforts studying the electroactive bacterium Shewanella oneidensis, we will first select for new-to-nature reactivity by engineering electron transfer proteins that couple the desired chemical reaction to cell growth. We hypothesize that EET can significantly accelerate the rate of new biological reaction discovery. Next, we will examine the role of EET in the healthy and diseased gut microenvironment. We hypothesize that EET contributes to iron homeostasis and will explore this possibility by combining animal models of gut dysbiosis with a novel droplet microfluidic assay capable of detecting electroactive bacteria in complex ex vivo samples. Finally, we hypothesize that electroactive probiotics can facilitate EET-driven health outcomes. Towards this goal, we will transfer EET-capable proteins to therapeutically relevant bacterial hosts and lay the groundwork for future in vivo and therapeutic applications that exploit our understanding of EET’s role in disease biology. Overall, our proposal will examine the fundamental role of EET in human health and apply this knowledge toward advancements in biocatalysis and therapeutic development.