Population Regulation and Controlled Phage Release in Engineered Bacteria for Eradication of Pathogens

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Ursula Florjanczyk

University of Toronto, Canada

Synthetic biology tools allow for the design of novel therapeutic bacteria as an alternative treatment to antibiotics in controlling outbreaks of pathogenic microbes. One approach is to develop engineered bacteria (EB) as a method to target phage release to attack and eradicate pathogens. Phages make an attractive option for treatments due to their relatively narrow range of viable hosts and potential for self-perpetuation. Detection of the target microbes can be used to regulate lysis of EB cells and release of phages by engineering the bacterial cell-cell system; quorum-sensing. The development of these EB into therapeutic probiotics will demand inclusion of a component capable of auto-regulating population size to avoid out-competing native flora in host organisms. This component will also coordinate phage release in order to successfully overcome the target pathogen population. Placing the expression of a lethal gene under control of quorum-sensing creates an EB population that can maintain a tunable population density. Mathematical models that characterize the design of such a circuit that can balance population loss due to lysis and growth-regulation are outlined here. The models also elucidate the dynamics of EB populations in the presence of pathogens and the effect of tuning circuit parameters on population stability. Model outcomes are compared to preliminary in vitro results demonstrating the behaviour of our EB. Exploring the dynamics of this complex synthetic circuit will provide essential insight into the challenges present when designing therapeutic microbes.