Reprogramming Microbes to Be Pathogen-Seeking Killers
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Abstract
Recent
examples of new genetic circuits that enable cells to acquire
biosynthetic capabilities, such as specific pathogen killing, present
an attractive therapeutic application of synthetic biology. Herein,
we demonstrate a novel genetic circuit that reprograms Escherichia coli to specifically recognize, migrate
toward, and eradicate both dispersed and biofilm-encased pathogenic Pseudomonas aeruginosa cells. The reprogrammed E. coli degraded the mature biofilm matrix and killed
the latent cells encapsulated within by expressing and secreting the
antimicrobial peptide microcin S and the nuclease DNaseI upon the
detection of quorum sensing molecules naturally secreted by P. aeruginosa. Furthermore, the reprogrammed E. coli exhibited directed motility toward the pathogen
through regulated expression of CheZ in response to the quorum sensing
molecules. By integrating the pathogen-directed motility with the
dual antimicrobial activity in E. coli, we achieved signifincantly improved killing activity against planktonic
and mature biofilm cells due to target localization, thus creating
an active pathogen seeking killer E. coli