(156a) Synthetic Antibacterial Probiotics

Foodborne bacterial gastrointestinal infections are significant causes of morbidity and mortality worldwide. Alarmingly, because of the extensive, non-therapeutic use of antibiotics in agriculture, foodborne pathogens are emerging that are resistant to our most potent drugs.

We pursue an integrated research approach to reduce the use of therapeutic antibiotics in animal feed and treat gastrointestinal infections in animals and humans. We employ synthetic and systems biology technologies to engineer probiotic bacteria that reside in animal gastrointestinal tracts, and then express and release antimicrobial peptides (AMPs). Probiotic bacteria are part of the gastrointestinal microbiota and have known benefits for humans and animals. AMPs are proteins and can be readily produced by bacteria. What is unique in our approach is the use of synthetic biological switches to precisely control the overexpression and delivery of AMP molecules.

AMPs are small molecules with remarkable bactericidal properties. Their use has been limited because they are quickly degraded by the host if administered orally or intravenously. We use probiotics as AMP-delivery vehicles. Probiotics are bile-resistant microorganisms that can be delivered safely in food or water. We engineer inducible AMP expression systems in probiotics. We examine the impact of controllable delivery of AMPs in swine and poultry challenged by infectious agents and explore AMP-carrying probiotics as alternatives to traditional antibiotics in agriculture. We also experiment with mice as models of human gastrointestinal tracts.

 

We use established protein expression systems in probiotic bacteria to express bacteriocins, AMPs that are naturally produced by bacteria. We also study pathogen-specific AMPs. We experiment with probiotic species Lactococus lactis, Lactobacillus acidophilus, known to be safe for consumption by animals and humans. These species are also well-annotated with known genomes and have established microbiological and genetic engineering techniques. Synthetic molecular devices are engineered to be robust. With established metagenomics, proteomics and bioinformatics techniques, we then analyze animal gut microbiomes and the relationships between probiotics, commensal microbes and health. We quantify the presence of engineered probiotics and of expressed AMPs in intestines, and quantify the disease outcome for animals challenged by pathogens.