November 21, 2011
Targeted Antibacterial Proteins May Offer Antibiotic Alternative
New publication demonstrates ability of Avidocin proteins to prevent and treat E. coli O157 diarrhea in animal study
A novel antibacterial protein targeted against E. coli O157:H7 may offer a way to prevent or treat serious food-borne bacterial infections, as demonstrated in a study published in the December issue of Antimicrobial Agents and Chemotherapy. Results in an animal model of E. coli infection showed that the orally administered protein, developed by AvidBiotics, Inc., could prevent or treat E. coli O157:H7-induced diarrhea and intestinal inflammation when administered either on a preventative basis or after the onset of diarrhea. Moreover, animals treated with the protein also carried and shed fewer of the E. coli O157:H7 bacteria in their feces.
"E. coli O157:H7 contamination of foods like ground meats or produce is a well-publicized public health problem, with life-threatening infection outbreaks reported around the world in recent years," said Dean Scholl, Ph.D., lead author of the publication. "Antibiotics are contraindicated for patients infected with enterohemorrhagic E. coli (EHEC) strains like O157:H7, because many of those drugs induce the bacteria to produce and release harmful toxins. Anti-diarrheal medications also do not benefit infected patients, as they cause the bacteria to be retained in the intestines, leading to greater toxin exposure. Thus the successful development of treatments that can prevent infection or limit symptoms and disease duration and the possible further spread of harmful bacteria without increasing toxin release could benefit both individual patients and affected communities."
The study published by Dr. Scholl and his collaborators at AvidBiotics and Brigham and Women's Hospital/Harvard Medical School assessed AvidBiotics' anti-E. coli O157 protein, termed an Avidocin protein, in a rabbit model of infection and reported that:
The Avidocin protein remained active within the treated animals' intestinal tract for at least 24 hours post administration.
When given shortly after the animals were infected with E. coli O157:H7 but before they developed active disease, the Avidocin protein inhibited bacterial colonization and/or the symptoms of infection. Animals that received the highest dose of protein studied did not develop diarrhea at any time during the experiment. In contrast, animals given buffer alone developed typical diarrhea within 1-2 days after infection, which worsened by the 3rd day of the study.
Analyses of colon tissue showed less severe intestinal inflammation in Avidocin protein-treated animals compared to controls. Avidocin protein administration also greatly reduced the number of E. coli O157:H7 recovered from the intestine and the stool of treated animals.
When the anti-E. coli O157:H7 Avidocin protein was administered to infected animals already exhibiting disease symptoms, the existing diarrhea began to resolve in treated animals compared to animals treated with placebo. This reduction in diarrhea persisted until the experiment was terminated, 9 days post infection, at which time the feces of the treated animals appeared closer to feces from uninfected animals than the still largely liquid stool of the control animals. Thus, even after the onset of diarrhea in E. coli O157:H7-infected animals, administration of the anti-E. coli O157:H7 Avidocin protein could still mitigate the effects of infection.
"These findings suggest that an Avidocin protein targeted against E. coli O157:H7 offers promise for both the prevention and treatment of infection by this important enteric pathogen," concluded Dr. Scholl. "Moreover, this agent provides several significant advantages over conventional antibiotics, including a lack of drug-induced shiga toxin production and unintended collateral damage to normal intestinal bacterial populations. Additionally those rare variants of E. coli O157:H7 that emerge resistant to the anti-E. coli O157:H7 Avidocin protein are likely to have compromised virulence, or disease-causing properties."
About the Avidocin Protein Platform
AvidBiotics genetically engineers Avidocin proteins from R-type pyocins, antibacterial proteins produced by some Pseudomonas aeruginosa strains. These proteins specifically kill bacteria by binding to the bacterial cell and punching a hole in the cell envelope, causing membrane depolarization and ultimately cell death. AvidBiotics has previously demonstrated that Avidocin proteins can be engineered to recognize and kill in a highly targeted and specific manner a variety of bacteria, including E. coli, Salmonella, Shigella, Clostridium difficile, and Yersinia pestis (the bacterium that causes plague), thus serving as a platform for the production of numerous highly specific antibacterial agents.
AvidBiotics is also currently developing Avidocin proteins against Acinetobacter, a bacterium associated with serious, often broadly antibiotic-resistant infections in Intensive Care Units and those incurred by U.S. military deployed in Iraq and Afghanistan. In addition to the human health care uses of the Avidocin technology, AvidBiotics is collaborating with food safety and hygiene company EcoLab to develop antibacterial proteins for use against E. coli O157:H7 in meat processing.
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