(72f) Engineering Probiotic Bacteria to Help Us Fight the Emergence of Antibiotic Resistant Bugs

Gastrointestinal (GI) infections currently take a significant toll on human health and constitute a serious concern worldwide (1). The Centers for Disease Control estimates that more than 650 million people globally are affected each year by bacterial diarrhea (2). This number is rising as antibiotic use in agriculture is hastening the emergence of drug-resistant bacteria. The effectiveness of many antibiotics has been lost as the number of drug resistant bacteria strains increases. There is now a substantial overlap in between the classes of antibiotics listed as critically important for human health by the World Health Organization and the antibiotics listed as critically important for agriculture by the World Organization for Animal Health (3-5). Currently, it is estimated that over 70% of antibiotics produced in the United States are given to cattle, pigs, and poultry to improve feed efficiency at sub-therapeutic levels and in the absence of infection (6). This use favors the emergence of antibiotic resistant bacterial strains and ignites a significant threat to human health worldwide (5-7).

Herein, we present a new approach to reducing the widespread use of antibiotics in agriculture. This work has aimed to engineer probiotic bacteria strains with inducible antimicrobial peptide (AMP) expression systems. AMPs are small proteins with remarkable bactericidal character (8, 9) while probiotics are live bacteria that can be safely delivered to animal GI tracks as supplements in food or water (10, 11). To date, we have built inducible AMP expression systems in probiotic bacteria strains. We have characterized both their antimicrobial activity against specific pathogens of interest as well as their toxicity to host cells. We are currently working towards characterizing our systems in animal models. More specifically, we are seeking to quantify the changes in gut microflora driven by the administration of our engineered probiotics and evaluate their effectiveness and impact on animal health in the presence of pathogen challenges.

Our engineered probiotics will be optimized to a) improve overall animal health, and b) fight off bacterial infections by expressing AMPs only in the presence of pathogens or upon induction with a small molecule.

1. Turner SM, Scott-Tucker A, Cooper LM, & Henderson IR (2006) FEMS Microbiol Lett 263, 10-20.
2. Sanders JW, Putnam SD, Frankart C, Frenck RW, Monteville MR, Riddle MS, Rockabrand DM, Sharp TW, & Tribble DR (2005) Am J Trop Med Hyg 73, 713-719.
3. Barie P (1998) World Journal of Surgery 22, 118-126.
4. Domin M (1998) Br J Theatre Nurs 8, 14-18.
5.  (2007) Joint FAO/WHO/OIE Expert Meeting on Critically Important Antimicrobials Rome, Italy.
6. White W (1998) Science.
7. Mellon CB, KL Benbrook et al (2001) Union of Concerned Scientists.
8. Bolintineanu D, Hazrati E, Davis HT, Lehrer RI, & Kaznessis YN Peptides 31, 1-8.
9. Hancock RE (2001) Lancet Infect Dis 1, 156-164.
10. Pagnini C, Saeed R, Bamias G, Arseneau KO, Pizarro TT, & Cominelli F Proc Natl Acad Sci U S A 107, 454-459.
11. Van Niel CW, Feudtner C, Garrison MM, & Christakis DA (2002) Pediatrics 109, 678-684.