Toward Engineered Probiotics: Screening for Sensors and Antimicrobial Peptides in the Gut

The gut is home to the largest, most diverse collection of microbes that inhabit the human body. When functioning normally, this ecosystem benefits the host by producing micronutrients and harvesting energy from food. Disruptions to this normal functioning—so-called gut dysbiosis—have been linked to inflammatory bowel diseases, obesity and cancer. Despite the prevalence of infectious gut diseases, our ability to administer specific, effective treatments is limited. Broad-spectrum antibiotics exacerbate gut dysbiosis and encourage the emergence of multiple drug resistant pathogens. Engineered probiotic bacteria have the potential to transform this paradigm by local secretion of targeted, non-toxic therapeutics. We have engineered E. coli to secrete microcin E492 (MccE492), a siderophore-linked antimicrobial peptide from Klebsiella pneumoniae. This engineered E. coli strain inhibits the growth of pathogenic strains of Salmonella and E. coli in vitro. Ongoing work will focus on i) augmenting the capability of this rudimentary probiotic by incorporating pathogen- and infection-specific sensors and ii) performing functional and bioinformatic screens for novel antimicrobial peptides with activity in the gut.