Engineering a Probiotic B subtilis to Prevent C difficile-Associated Hospital-Acquired Infection
Abstract
Clostridium difficile is an opportunistic bacterial pathogen that causes gastrointestinal disease that ranges from mild diarrhea to life-threatening inflammation of the intestines, known as colitis. C. difficile is resistant to most antibiotics and easily proliferates in the gut of antibiotic-treated patients whose normal gut microflora has been severely reduced. This usually happens in the hospital setting when a patient receives large doses of antibiotics for a surgery, which kills the "good" intestinal bacterial and allows unregulated growth of C. difficile. The incidence, mortality, and associated healthcare costs of C. difficile associated disease (CDAD) is reaching historic highs. The rising frequency and severity of CDAD and the high probability of recurrence require novel or alternative antimicrobial therapies to treat C. difficile. Endolysins are enzymes that can chew up the bacterial cell wall upon contact and represent an alternative antimicrobial approach to antibiotics. Moreover, these enzymes act in a species-specific manner. They can be selected to only kill pathogenic bacteria (i.e., C. difficile) and not harm "good" bacteria in the intestines. Nonetheless, the high acidity of the stomach poses a significant challenge to delivering these enzymes to the intestines. Toward this end, one can use a probiotic (i.e., a beneficial bacteria) to deliver these endolysins to the intestines. A particular Bacillus bacterial species is known to pass through the stomach in the form of a spore, and then harmlessly grow and inhabit the human intestines. Because of this, it has been used as a probiotic in Europe and Asia for years. This proposal aims to bioengineer the Bacillus probiotic to deliver a C. difficile-specific endolysin that will be secreted in the intestines to control C. difficile in a mouse infection model. The data obtained in these studies will enhance the understanding of probiotic bioengineering and of the potential for using Bacillus spores as a safe and effective vehicle for delivering prophylactic and/or biotherapeutic agents directly to the gut as a treatment for hospital-acquired infections such as CDAD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610075
Entities
People
- Daniel C Nelson
Organizations
- United States Army
- University of Maryland