Engineering bacterial therapeutics with enhanced metabolic properties

Our understanding of the human gut microbiome is increasing at a rapid pace, to the point where important metabolic interplay between components of the community are now understood. Antibiotic treatment, which selectively removes subset of species from the gut, results in metabolic imbalances of sialic acid and other sugars that can be exploited by important pathogens such as Clostridium difficile and Salmonella enterica to enable colonization. The development of CHAIN Biotech’s Clostridium Assisted Drug Delivery (CADD) platform relies on the delivery and germination of spores in the human gut leading to cell growth enabling the synthesis and delivery of a payload. In this BBSRC iCASE project, we will study the metabolic potential of the species C. butyricum, which includes the CADD organism, through comparative genomic analysis of metabolic pathways and metabolic phenotyping to assess which gut-relevant carbon or nitrogen sources are likely being used for outgrowth in the anaerobic colon and subsequent colonization. The specific energy sources used by the organism are currently unknown, but will likely include monosaccharides, peptides, amino acids and fatty acids. This information can then be used to engineer or evolve strains that might enable prolonged or alternatively reduced residence time of the CADD organism in the gut. Specifically, we will engineer the ability to rapidly uptake and catabolize sialic acid to short chain fatty acids and will then investigate the potential of CADD to deliver this novel metabolic payload to help prevent pathogen colonization post-antibiotic treatment. These experiments will also allow us to learn more about transport and catabolic pathways for sialic acids in the human gut and will use a combination of microbiological, biochemical and bioinformatics techniques used widely in the Thomas lab.