Helicobacter pylori (H. pylori) is a gram-negative bacterial pathogen that, as of 2015, resided in the gastrointestinal tract of an estimated 50% of the world’s population1, largely affecting developing countries and communities. H. pylori colonizes the gastric mucosa in the stomach, and infections are linked to mucosal lymphoma, gastritis, the formation of peptic ulcers, and gastric cancer2, even in asymptomatic individuals. Furthermore, certain lifestyles or exposures can trigger increased virulence and aggression towards the host. H. pylori has a unique set of evolutionary adaptations that allow it to colonize the stomach very effectively, making treatment difficult. The current standard of care is multiple rounds of a multi-drug cocktail including potent broad-spectrum antibiotics, proton pump inhibitors. These treatments are extremely harsh on patients’ bodies and intestinal microbiomes, and only somewhat effective, varying widely depending on drug choice with a pooled eradication rate of 79%3.
Our solution to the inefficacy of current treatments is an engineered, probiotic strain of E. coli (Nissle 1917) that possesses bactericidal characteristics specific to H. pylori. Nissle 1917 is already used as a probiotic(for competitive colonization and microbiome balance), and in the US is sold under the brand name Mutaflor ®, and has been granted Generally Recognized as Safe (GRAS) status by the FDA. Our engineered strain will differ by specifically recognizing H. pylori cells and delivering a malicious DNA payload through horizontal gene transfer. This malicious plasmid will inhibit H. pylori biofilm formation, forcing it into the more vulnerable motile growth form, and promote intraspecific horizontal gene transfer to spread our payload throughout the H. pylori population, killing the pathogenic cells.
We are taking a uniquely modular approach that will allow future work to modify our platform to be targeted towards nearly any pathogenic GI tract bacteria, and allows us to develop these parts in parallel. Other common pathogen examples, such as Salmonella typhi(responsible for typhoid fever) and Enterotoxigenic E. coli, could also be targeted using our potential system.
By engineering a variety of biological systems for stomach colonization, navigation to H. pylori, and conjugation to deliver a fatal DNA payload, we are able to create an E. coli-based therapeutic that is specific, modular, and safe. Our E. coli-based solution does not rely on the use of antibiotics, which can be harmful when used repeatedly in high doses, and are becoming increasingly ineffective against bacterial infections3.Future directions: