Phage Therapy to Treat Clostridium difficile-associated Diarrhea

We are all exposed to bacteria. ‘Good bacteria’ are necessary for our good health and the immune systems of healthy people normally fight off invading bacteria successfully.

But for those with debilitated health, the infection is too great, or the patient too weak, perhaps because of a compromised immune system, as is the case for those living with HIV/AIDS or receiving cancer treatment. In these situations and also in the very young and very old, opportunistic infections can prove fatal.

For more than 50 years, we have relied on antibiotics to treat the bacterial infections. The result has been a gradual rise in antibiotic resistance and some bacteria are resistant to most, if not all, antibiotics and antimicrobials.

C. difficile is an opportunistic pathogenic bacterium which causes bowel infection accompanied with abdominal pain, various degrees of diarrhea and in the more severe cases, pseudomembranous colitis and sometimes death. It is common in certain parts of Canada; and a growing problem in our hospitals.

Phages are viruses which kill bacteria without harming people. They were first discovered in 1917 by a Canadian, Félix d’Hérelle. Phages have been used in Eastern Europe with impressive case reports but there is a clear lack of rigorous scientific analyses of their use to treat human disease.

Phage therapy to treat Clostridium difficile-associated Diarrhea (CDAD) would have the advantage of preventing, or at least minimizing, antibiotic use and possible resistance. In addition, it would be relatively easy to adapt phages to follow the evolution of particular strains, and short-term applications could be possible.

The objective of this grant is to do fundamental research to deepen our understanding of phages infecting C. difficile and phage-encoded endolysins, which could potentially be used as antimicrobial agents to treat CDAD.

Researchers will:

1. isolate virulent phages in nature (e.g. hospital sewage, city water treatment facility) using the most predominant C. difficile isolates as test strains
2. isolate temperate phages by inducing prophages from a collection of C. difficile isolates
3. characterize the isolated phages at the microbiological and molecular level, including sequencing the whole genome of a number of selected phages
4. clone, sequence and characterize phage endolysins and assess their effectiveness to kill C. difficile in vitro.

Impact of the Research

Phage therapy represents an alternative with real potential to fight multidrug-resistant pathogens. The present study represents a great opportunity to assess the potential of phage therapy to treat CDAD.

The wider host spectrum of endolysins compared to phages could make it possible to use them to kill any strain of C. difficile, independent of its genotype. It could possibly be used in conjunction with phages to increase the effectiveness of the therapy.

On the long ¬term, this study could lead to significant improvements of the health and quality of life of the Canadian population and the healthcare system could be alleviated from an important financial burden.

Researcher: Louis-Charles Fortier, Ph.D
Recent publication: Fortier LC* and S. Moineau. Morphological and genetic diversity of temperate phages in Clostridium difficile. Appl. Environ. Microbiol. 2007 Sep 21; [Epub ahead of print] * Corresponding author http://www.usherbrooke.ca/microbiologie/Professeurs/fortier.htm

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© 2011 CFID.