Establishment of Bacteroides as a synthetic biology chassis

• Applicant: Dr. Isabel Kolinko
• Subject Area: Microbial Ecology and Applied Microbiology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279290315

Engineering of microbial cells to act as 'smart' therapeutic entities for the treatment of various diseases has recently emerged as an important subfield in synthetic biology. So far, mostly model systems with a well established genetic toolbox were used for the implementation of therapeutic functions. In contrast, the potential of using prevalent commensals naturally colonizing a specific body niche, which should have more amenable host interactions, has not been exploited so far. In the human gut, various Bacteroides species have been found to productively interact with the host by processing indigestible carbohydrates, contributing to the host-microbiome homeostasis, and by conferring protection from inflammatory diseases. To pave the way for their use as cell therapy systems, the aim of this project is to establish the cultivable and genetically tractable species B. fragilis and B. thetaiotaomicron as synthetic biology chassis. To achieve this goal, I propose to construct a novel Bacteriodes toolbox. This toolbox will include inducible expression systems for the spatiotemporally controlled production of recombinant proteins. Furthermore, secretion systems will be rewired or heterologously synthesized to ensure targeted export of various bioactive molecules. The functionality of the constructed expression and secretion systems will be evaluated by the implementation of a genetic circuit for the production and secretion of the new drug Linaclotide, which has recently been approved for the treatment of irritable bowel syndrome. The proposed project will contribute to the foundational understanding of transcriptional regulation as well as secretion mechanisms in Bacteroides. Ultimately, it has direct applications in the development of Bacteroides as biosensors and synthetic cell therapy systems.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professor Dr. Michael Fischbach; Professor Wendell Lim, Ph.D.