Researchers at a Bay Area startup are looking in sewage for a substitute for antibiotics.

With the well-documented rise in antibiotic-resistant bacteria, EpiBiome’s efforts are part of a renewed interest in bacteriophages, viruses that address specific strains of bacteria, to cure infections.

It’s not the first time medical solutions have been sought in the sewer: Cephalosporins, an early class of antibiotics, were discovered in Sardinian wastewater in the 1940s.

Some 23,000 people in the U.S. die every year from antibiotic-resistant infections, according to the Centers for Disease Control and Prevention. As more bacteria become resistant to available drugs, infections that are trivial now could become deadly.

The research into bacteriophages, commonly known as phages, by the fledgling Union City company and others “is all being driven by the recognition that the drugs that we have right now and the very few drugs that exist in the (development) pipeline may not by themselves be sufficient to address drug resistance,” said Dr. Randall Kincaid, a senior scientific officer with the National Institute of Allergy and Infectious Diseases.

Looking for answers in bacteriophages makes sense, said Nick Conley, EpiBiome’s president.

“Bacteriophages are nature’s way of dealing with bacteria,” he said. “Rather than us fighting nature, let’s pit nature against itself.”

Brilliantly simple

In some ways, phages are brilliantly simple, he said. They are the most abundant organisms on Earth. They evolved alongside bacteria as their natural enemy, and they kill half the bacteria on the planet every two days. Although phages had been used in the past, the emergence of antibiotics seven decades ago made them all but forgotten to Western medicine.

For now, the startup has turned its attention to creating a viral phage cocktail to treat a particular kind of infection in cows’ udders that costs the U.S. dairy industry up to $2 billion annually. EpiBiome researchers hope to isolate the right phages from sewage and farm water runoff and pit them against bacteria to treat the cows.

While much is still unknown, the hope is that similar treatments could someday be used in humans.

Unlike antibiotics, which kill both bad bacteria that cause disease and the good bacteria that fight infection and help digest food, bacteriophages target specific bacteria. They latch on, inject their own DNA, hijack the bacteria to create hundreds of copies of themselves and explode the bacteria’s cell, escaping. Those copies repeat the process, killing more bacteria.

“It’s like a smart bomb. You have your target and it’s highly selective,” said Dr. Henry Chambers, a professor of medicine at UCSF.

Government agencies in the U.S. and Europe have shown interest in studying phages. The National Institute of Allergy and Infectious Diseases noted phage therapy as one of seven potential ways to fight antibiotic resistance, and the European Union recently contributed $5.2 million to a study that will attempt to break down regulatory barriers by proving phage treatment for infected burns in humans is safe and effective.

A French Canadian microbiologist discovered phages in 1917 and successfully treated a 12-year-old boy’s dysentery in a Parisian hospital two years later. Phages were widely used in early 20th century medicine - even manufactured by the pharmaceutical company Eli Lilly - until antibiotics came into vogue in the 1940s.

Phage therapy virtually disappeared in the West, but behind the Iron Curtain, use of phages continued through the 20th century. Phages are still used to treat bacterial infections in Russia, Poland and Georgia.

In the absence of adequate published research and clinical trials, phages are a long way from passing U.S. Food and Drug Administration muster for human use, though the FDA and the U.S. Department of Agriculture have allowed phage products that kill bacteria in food preparation. Successful animal trials could help turn the scientific community’s head, though, Chambers said.

Starting at the farm

That’s where Conley and his team hope to come in. Their process starts at the farm, where they collect samples of bacteria that cause mastitis, the infection that inflames cows’ udders, diminishing milk production and quality. Despite iodine sprays designed to fight the disease, between 40 and 90 percent of any given herd ends up infected with the disease, Conley said.

To find phages that kill the mastitis-causing bacteria, the team collects farm water runoff and sewage.

“Anywhere you find bacteria, you will actually find the viruses - the phages - that infect them,” Conley said.

Back in their lab, EpiBiome’s researchers spin down the dirty water in a centrifuge to get to the phages, which they select until they get the best fit to kill bacteria. If the virus doesn’t work, they can add more to create a phage cocktail that targets multiple bacteria.

Conley showed slides of a dish covered in mastitis bacteria before and after it was streaked with phage. The virus had attacked and killed the bacteria in its path. Left to its own devices, the phage would kill the remaining bacteria.

Plants and cows are one thing. Humans are another, said Chambers. Some scientists are concerned that humans could have allergic reactions to phages or that bacteria could eventually mutate to become resistant to them, although some believe that since the phage supply is nearly limitless, adding phages to a cocktail could solve the problem.

“Intellectually and theoretically, it has a lot of upsides, but there are huge practical limitations and unknowns, but is it worth throwing 5 million bucks at? Probably,” Chambers said.

The success of phage therapy in Eastern Europe and long ago in the West isn’t enough to get phages approved for human use in the U.S., where the treatment would have to be proved safe through the FDA’s rigorous clinical trial process. AmpliPhi Biosciences Corp., a Virginia company, hopes to start clinical trials in humans next year, said spokeswoman Danielle Lewis.

Big plans for future

Up to this point, the EpiBiome team has only proved that its phage can kill a strain of mastitis bacteria in the lab. But they hope to move forward quickly. Last week, the startup was accepted into the Illumina Accelerator Program, which aims to advance the study of genomics. That prize comes with funding, mentoring and the use of advanced lab equipment.

Conley hopes to begin to testing an aerosol phage spray on dairy herds soon. If all goes according to plan, he said he is interested in working on human applications.

“There’s a huge amount of money to be made in solving this (dairy cow) problem, but the real opportunity is in human medicine,” he said. “Everything that we do is directly applicable, the workflow is directly applicable to using phages in human medicine.”