South San Francisco, CA (March 14, 2012): A highly targeted bactericidal protein against the life-threatening foodborne E. coli O104 strain was rapidly created using AvidBiotics’ antibacterial Purocin™ protein technology, making use of rapidly acquired, published, draft genomic sequence data as detailed in a new publication in PLoS ONE. The strategy described offers a rapid-response platform with the potential to create targeted agents for use against emerging bacterial pathogens within days-to-weeks of acquiring the pathogen’s genome sequence.

“AvidBiotics has created a highly versatile technology platform for the generation of antibacterial proteins that specifically target and rapidly kill bacterial strains, offering important benefits in food security,” said AvidBiotics’ scientist, Dean Scholl, Ph.D., lead author on the new publication. “In collaboration with scientists from the U.S. Department of Agriculture, we’ve now shown that we can quickly generate such Purocin™ proteins against an emerging pathogen using only data acquired from its genome sequence, without necessarily having immediate access to the pathogen itself. This technology, in combination with the ever-increasing speed in which genome sequences can be generated and DNA synthesized, should provide a valuable tool for responding to newly emerging, re-emerging, and ever-changing bacterial threats.” The E. coli O104 strain, which initially emerged in Germany in spring 2011, was ultimately responsible for close to 4,000 illnesses and 48 deaths.

The AvidBiotics authors and their collaborators at the U.S. Department of Agriculture, Western Regional Research Center, describe how, using published genomic data from the German E. coli outbreak strain, they identified an O-antigen-specific prophage tail spike protein encoded in the pathogen’s genome. They synthesized the identified gene and fused it to the tail fiber gene of an R-type bacteriocin (a defense protein produced by certain bacteria against competing strains), and expressed the novel, engineered, antibacterial protein so that the tail fiber fusion was incorporated into an R-type bacteriocin structure. The resulting engineered protein demonstrated the ability to specifically bind and rapidly kill all tested E. coli strains that produce the O104 lipopolysaccharide antigen, including the German outbreak strain isolated from affected patients. None of many tested E. coli strains lacking the O104 antigen was sensitive to the O104-targeted protein, ensuring no unintended collateral damage.

About the AvidBiotics Antibacterial Protein Platform

AvidBiotics genetically engineers bactericidal proteins from R-type bacteriocins, proteins produced by some Pseudomonas aeruginosa strains for the purpose of killing competing bacteria. AvidBiotics’ antibacterial proteins specifically kill bacteria by binding to the bacterial cell and punching a hole in the cell envelope, causing membrane depolarization and rapid cell death.

AvidBiotics has previously demonstrated that Purocin™ proteins can be engineered to recognize and kill in a highly targeted and specific manner a variety of bacteria, including E. coli, Salmonella, and Shigella, thus serving as a platform for the production of numerous highly specific antibacterial agents. AvidBiotics is collaborating with food safety and hygiene leader, Ecolab Inc. (NYSE: ECL), to develop antibacterial proteins for use against E. coli O157:H7 in processing meat and other foods.

In addition to E. coli, a cause of both serious diarrheal disease and recurrent urinary tract infections, AvidBiotics is also currently developing Avidocin™ proteins against Pseudomonas aeruginosa, a common cause of severe pneumonia and wound infections, Clostridium difficile, the most common cause of hospital-acquired infections, and Acinetobacter, a bacterium associated with serious, often broadly antibiotic-resistant infections in Intensive Care Units and with injuries incurred by U.S. military deployed in Iraq and Afghanistan.

About AvidBiotics

AvidBiotics is a developer of novel, non-antibody proteins as targeted therapeutics against bacteria, viral infections and cancers. The scaffolds of AvidBiotics’ proteins exhibit functional potency, e.g. killing, exceeding that of antibodies. AvidBiotics has two proprietary product platforms. The first is this new class of tailorable, targeted bactericidal agents for use in the treatment or prevention of specific bacterial infections. The second specifically flags virus-infected or cancerous cells for enhanced destruction by the Natural Killer and T-cells of the potent innate immunity system. AvidBiotics focuses on human therapeutic applications of its technologies, both on its own and in partnership with governmental agencies and research institutions, while taking advantage of further near-term collaborative opportunities offered by specific applications of its products and technology platforms in areas such as food safety, biodefense and animal husbandry.

“DGRs offer a competitive advantage to many bacteria and bacteriophages in nature, as they allow them to quickly adapt and survive under challenging conditions,” said Dr. Miller. “The typical DGR can theoretically generate more than 10 trillion diverse genetic sequences at select sites in target genes. Thus, DGRs can potentially be used to generate molecular diversity for protein engineering applications that are not practical with currently available technologies.

“Our new publication not only describes new mechanistic information about DGRs, but it also offers a blueprint for the use of DGRs in protein engineering,” Dr. Miller concluded.

AvidBiotics, which has worldwide rights to the DGR technology, is working  to apply this technology to both its product development platforms, as well as leverage its value through collaborations and licensing arrangements.

The Diversity Generating Retro-element (DGR) System is well suited for a variety of protein engineering applications, offering such advantages as:

• No need for repeated cycles of cloning and transformation as in phage display
• Mutagenesis “homes in” on specific amino acid positions of interest, not random ones, in the target protein
• A host bacterium does all the diversification “naturally”
• Diversification can be serially and cumulatively repeated without degeneration of the genetic mechanism or the protein scaffold

In addition to providing a tool for use with AvidBiotics’ targeted antibacterial and antiviral/anti-cancer product platforms, the DGR system could be applied to

• Protein engineering by optimizing or modifying particular sites of interest, applicable to any scaffold
• Generation of highly specific protein diagnostics to detect most any “analyte”
• Generation of reagents for product recovery processes
• Creation of kits and reagents for research laboratory use in protein engineering

About AvidBiotics

AvidBiotics is a developer of novel, non-antibody proteins as targeted therapeutics against bacteria, viral infections and cancers. The scaffolds of AvidBiotics’ proteins exhibit functional potency, e.g. killing, exceeding that of antibodies.  AvidBiotics has two proprietary product platforms. The first is a  new class of tailorable, targeted bactericidal agents for use in the treatment or prevention of specific bacterial infections. The second specifically flags virus-infected or cancerous cells for enhanced destruction by the Natural Killer and T cells of the potent innate immunity system.  AvidBiotics focuses on human therapeutic applications of its technologies, both on its own and in partnership with governmental agencies and research institutions, while taking advantage of further near-term collaborative opportunities offered by specific applications of its products and technology platforms in areas such as food safety, biodefense and animal husbandry.

South San Francisco, CA: 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.

About AvidBiotics

AvidBiotics is a developer of novel, non-antibody proteins as targeted therapeutics against bacteria, viral infections and cancers. The scaffolds of AvidBiotics’ proteins exhibit functional potency, e.g. killing, exceeding that of antibodies.  AvidBiotics has two proprietary product platforms. The first is this new class of tailorable, targeted bactericidal agents for use in the treatment or prevention of specific bacterial infections. The second specifically flags virus-infected or cancerous cells for enhanced destruction by the Natural Killer and T cells of the potent innate immunity system. AvidBiotics focuses on human therapeutic applications of its technologies, both on its own and in partnership with governmental agencies and research institutions, while taking advantage of further near-term collaborative opportunities offered by specific applications of its products and technology platforms in areas such as food safety, biodefense and animal husbandry.

Just in time for the holidays, researchers at Harvard Medical School’s Brigham and Women’s Hospital and AvidBiotics said Monday that the South San Francisco-based company’s Avidocin proteins could prevent and treat E. coli-related diarrhea and intestinal inflammation in animals.

If the Thanksgiving table conversation turns staid, you can find the results of the study in the December issue of the journal Antimicrobial Agents and Chemotherapy.

I spoke with Jim Knighton, co-founder and president of the “nine-people-and-a-dog” company, about the company’s food safety program, a key partnership and the new study.