The trillions of microbes that live inside the human gastrointestinal tract are suspected of playing a role in disorders as varied as obesity, asthma, and diabetes. Scores of scientists are studying such possibilities at biomedical research companies and in collaborations such as NIH’s Human Microbiome Project.
But can these diseases be caused by a single rogue germ in the gut, or do the illnesses take hold because the overall balance of a person’s microbial ecosystem has gone awry?
Researchers are trying to pull South San Francisco, CA-based AvidBiotics into such inquiries, because its technology platform might help answer the questions, says company president James Knighton. AvidBiotics is developing antibacterial proteins that can kill specific strains of bacteria in the gut without harming others—something most traditional antibiotics can’t do.
“You could selectively take out a bug, then look at what happens disease-wise to the experimental animal,” Knighton says.
Knighton is open to the idea of using AvidBiotics’s novel proteins as research tools, but the private company’s main goal is to develop narrowly targeted treatments that would cure or prevent infections with potentially lethal gastrointestinal microbes such as the bacterium Clostridium difficile.
That pathogen, also known as C. difficile, was one of the top three urgent threats named by the Centers for Disease Control and Prevention in a 2013 report on the problem of antibiotic resistance in pathogens. Infections with C. difficile can be treated with “broad-spectrum” antibiotics such as vancomycin, but these drugs also kill other microbes in the gut that probably support health. And the C. difficile infection frequently returns, causing diarrhea, colitis—a painful inflammation of the large intestine—and repeated hospitalizations. Nearly 250,000 people end up in US hospitals with C. diﬃcile infections every year, and at least 14,000 Americans die annually, the CDC estimates.
AvidBiotics has been testing the effectiveness of its bactericidal proteins called “diffocins” against C. difficile in mice.
“It only kills the target organism,” says AvidBiotics CEO David Martin. “It doesn’t disturb the microbiome.” The company is beginning to develop a manufacturing process for the proteins, which can be formulated as pills taken by mouth. It recently received a US patent on its “diffocin” antibacterial proteins and other inventions. The company plans to seek FDA permission to start clinical trials of its diffocin in 2015.
If one of the diffocin drugs is successful in clinical trials, it could replace a remedy used in people with recurrent C. difficile infections, Knighton says. The treatment, called a fecal transplant, is effective but it has a “gross factor,” he says. The patient receives a transplant of fecal matter from a healthy individual, which can re-establish a healthy microbial population in the recipient’s GI tract.
The success of fecal transplants has encouraged some companies such as San Bruno, CA-based Second Genome to pursue strategies to treat the whole microbiome rather than attacking a single pathogen directly. Second Genome is exploring ways to thwart C. difficile with modulating agents that keep the microbial ecosystem balanced, so it can suppress a bloom of the dangerous bacteria.
AvidBiotics still aims to kill bacteria directly, but hopes to eliminate the problems associated with conventional antibiotics. For one thing, most antibiotics cause collateral damage to the larger population of microbes while they attack a target pathogen. AvidBiotics, by designing proteins to destroy only a specific bacterial strain, is trying to make anti-infective drugs part of the “precision medicine” movement now mostly associated with targeted cancer therapies.
The company, incorporated in 2004, is making use of weapons that evolved inside the genomes of bacteria as much as 500 million years ago, Martin says. Some bacteria contain genes that are probably the vestiges of ancient attacks by enemy viruses called bacteriophages, he says. These viruses left behind some of the genes for their tail structures, and the host bacteria, at some point in evolution, began to use these tail proteins as defensive measures against competing microbes. The vestigial viral genes code for proteins that can injure certain bacteria.
AvidBiotics creates basic antibacterial protein “scaffolds” using genes from C. difficile and another bacterial species, Pseudomonas aeruginosa. The company then fuses onto the scaffold a portion of a viral tail structure that makes the protein complex into an effective weapon against a specific kind of bacteria.
Using this mix-and-match platform, AvidBiotics has produced a stable of bactericidal agents it calls Avidocin proteins. In addition to C. difficile, these proteins target other bacterial pathogens that include E. coli and species of Salmonella and Acinetobacter.
The Avidocins might turn out to be safer drugs against a tricky E.coli strain that is frequently the culprit in serious outbreaks of food poisoning, Martin says. Antibiotics can make the infection worse in children, because the drugs provoke the bacteria to release the dangerous Shiga toxin, he says. Avidocins, on the other hand, injure bacteria through a component of the protein complex other than the tail fiber. It’s a minuscule straw-like structure that pierces the cell wall. The hole is so small that the fairly sizeable bacterial toxins can’t get out, Martin says.
“These are remarkable nanomachines,” he says of the proteins. “They’re targetable hole-punchers.”
While AvidBiotics was pursuing human therapeutics, the US Department of Agriculture asked the company to apply its technology to food safety. The company now has a second line of potential products called Purocin proteins, and a collaboration with DuPont Nutrition & Health (NYSE: [[TICKER: DD]]) on food processing agents. One possible product for DuPont is a spray liquid that could control Salmonella contamination of meat from poultry.
“They’re funding us at a significant level,” Martin says.
AvidBiotics can also apply its protein platform to veterinary medicine—another possible way to bring in revenues from the technology while the company continues work on human therapeutics and prophylactic treatments, Martin says. The company has raised about $25 million to date from individual investors and government research grants, Knighton says. It has 15 employees.
In the arena of C. difficile treatments for people, AvidBiotics would be competing with Lexington, MA-based Cubist Pharmaceuticals (NASDAQ: CBST), which markets a novel antibiotic, fidaxomicin (Dificid) that was approved by the FDA in 2011 for the treatment of diarrhea caused by a C. difficile infection. Fidaxomicin was developed by San Diego, CA-based Optimer Pharmaceuticals, which Cubist acquired last year.
Cubist markets fidaxomicin as a narrow-spectrum antibiotic that wipes out C. difficile with minimal damage to other intestinal microbes. In clinical trials, participants taking fidaxomicin had fewer recurrences of C. difficile infection than those who took the conventional antibiotic vancomycin. Cubist and Optimer reported total revenues of $15.8 million from sales of fidaxomicin in the US and Canada during the fourth quarter of 2013.
Cubist’s drug, however, can promote the development of antibiotic resistance. Doctors are advised to prescribe it only when a patient has a known or strongly suspected C. difficile infection.
AvidBiotics hopes to prove that its Avidocin proteins will not increase the resistance of human gut bacteria to antibiotics. Drug resistance is a mounting problem in healthcare, and especially in hospitals. Bacteria readily acquire genes for antibiotic resistance by a number of means, such as viruses that can shuttle genes from one bacterium to another. In addition, the overuse of antibiotics kills off the bacteria that are vulnerable to the drug, allowing the resistant bacteria to multiply and dominate the microbial population.
Knighton says AvidBiotics’ bactericidal proteins could potentially be used to protect patients not infected with C. difficile from contracting the infection when they’re admitted to a hospital. The protein compounds might also be used as a preventive measure for hospital patients who already carry the dangerous bacteria, to suppress an explosion of the C. difficile population that might occur under the stress of surgery and treatment with antibiotics, Knighton says.
AvidBiotics was awarded a $600,000 grant from the National Institute of Allergic and Infectious Diseases of the National Institutes of Health in late 2012 to help advance its work on antibacterials targeted at C. difficile. The NIH has also supported the company’s work on the development of a second type of drug agent it calls Micasides.
These experimental compounds are designed to duplicate the natural protections of the human innate immune system against cancer cells and infected cells. These stressed cells normally produce proteins called MIC and display them on the cell surface. The MIC proteins are like flags to immune system cells such as natural killer cells, which rush to destroy the abnormal cells because they’re a threat to the host, Martin says.
But some cancer cells and infected cells manage to prevent the MIC proteins from appearing as surface signals. AvidBiotics is developing engineered human MIC proteins that stick to abnormal cells and also bind them to immune system cells that can destroy them.
“It’s a way of capitalizing on what nature has developed and trying to improve on it,” Martin says.
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