Establishing a synthetic biology toolbox for biosensor development in important probiotic host organisms.

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The fundamental impact of microbiome-based bacteria upon human health is increasingly understood. Dysbiosis is an imbalance of microbiome bacterial constituents that is strongly linked to the pathology of a wide range of conditions. This project will develop new approaches to rebalance the microbiome to treat and prevent such diseases. This project will engineer probiotic organisms to detect metabolic changes that are characteristic of pathologic states and trigger the deployment of appropriate treatments at the site of interest. This will require the development of engineering tools for probiotic lactic acid bacteria, as well as bioinformatics approaches to identify new sensing components required to create the required biosensors.We currently lack the tools necessary to detect and selectively remove bacterial constituents of the microbiome that cause dysbiosis. This limits therapeutic intervention. Novel, next-generation therapeutic bacteria (NTB) capable of sensing and precisely resolving dysbiosis represent a new frontier in the treatment of microbiome related disorders. This project will develop key dysbiosis-sensing components to create new bacterial therapies, by creating a biosensing toolbox enabling genetic engineering of lactic acid bacteria that can sense and react to metabolic changes characteristic of microbiome dysbiosis. Ultimately, these bacterial biosensors will control the deployment of specific bactericidal payloads into the microbiome by NTB.A bioinformatics approach will be taken to identify new sensing components that govern transcriptional regulation in response to external signals. These will then be repurposed as biosensors for the detection of the state of the microbiome. To better be able to engineer probiotic bacteria, a synthetic biology toolbox will be created for suitable hosts. For therapeutic use in the human microbiome, lactic acid bacteria such as Lactobacillus spp. are an ideal choice given their Generally Regarded As Safe (GRAS) status. However, few characterised promoters, ribosome binding sites, terminators and vectors are described for Lactobacillus spp., addressing this need will therefore transform our ability to reliably engineer these types of organism.