There's now a cleaner, better way to create viruses that kill antibiotic-resistant bacteria - Science

As harmful bacteria increasingly outwit antibiotics, some scientists are turning to a biological weapon to fight them: specialized viruses that slay bacteria. Now, a team of researchers based in Germany offers a potentially faster and better way to create these bacteriophages, or simply phages. Their method, which they dub a "phactory," produces phages without having to culture the bacteria they are directed against, and allows tweaking of the viruses to tailor them to specific antibiotic-resistant infections.

It's "a promising platform," says Pieter-Jan Ceyssens, a bioengineer at Sciensano, Belgium's national public health institute, who is responsible for quality control of phages that are already in use in several hospitals there and elsewhere. The advance comes as a major U.S. phage initiative is about to launch its first clinical trial, in cystic fibrosis patients plagued by chronic bacterial lung infections.

Phages were introduced as a weapon against bacteria more than a century ago. Western medicine abandoned them after the rise of antibiotics, but scientists and doctors in the former Soviet Union kept studying and using them. But for many clinicians, the production of phages still has the image of being sloppy, or an even "mystical" process, says Gil Gregor Westmeyer, a medical doctor and biological engineer at the Technical University of Munich (TUM) who led the phactory study, published last week in Cell Chemical Biology.

To obtain sufficient numbers of phages, pathogenic bacteria are typically first cultured in the lab. They are then exposed to phages that were previously isolated from the same pathogens. After these phages start to multiply in the bacteria, they are harvested and purified. Although this process has been made more efficient, clean, and reliable over the past couple of years, it remains a laborious and costly job. One problem is that bacterial cell walls often contain toxic compounds named endotoxins that need to be removed during the purification of phages, Ceyssens notes. "Not having to do that would really ease the production process," he says.

Last year, some of Westmeyer's TUM colleagues reported finding a possible alternative when they were exploring whether extracts from destroyed Escherichia coli cells still supported protein assembly. Not only did they, but the group further showed that this cell-free system, from which bacterial cell wall components were removed, could assemble whole, new E. coli–targeting phages if given the appropriate viral DNA and other molecules that allow the viral genes to be expressed.

In the new report, they show these E. coli extracts can produce viruses directed against other harmful bacteria, such as those that cause pneumonia or plague, if given the right phage DNA. "It is basically an entire pipeline for personalized phage treatment," Westmeyer says. "The only thing we did not manage to do was actually treat the patient we isolated the pathogen from, for regulatory reasons. But we did 'treat' the particular bacteria with the phage in the lab."

A startup founded by some of the TUM team members aims to expand the library of phages that phactory can assemble. "The phages described in the paper are relatively small, contrary to most of the phages directed against important multiresistant pathogens," Ceyssens says. Assembling the larger viruses might prove a challenge, he says, because some phages anchor themselves to the bacterial cell membrane in order to assemble copies. "I wonder if that will be possible with a soup of extracted E. coli cells, even if you would add those anchoring proteins," he says.

Another advantage of the team's approach is the ability to engineer the assembled phages and study the results in detail. They don't do this by changing the phage genome itself, but by adding to the soup DNA loops called plasmids that are independently translated to create modified phage proteins. These proteins are incorporated into the new viruses—but not into their progeny.

"To me, this part of the system has the most added value," says Robert Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics (IPATH) at the University of California, San Diego, School of Medicine. It gives researchers and clinicians the ability to tweak the phages, Schooley says, for instance to boost their power to destroy bacteria or the biofilms they produce.

IPATH is about to start its cystic fibrosis trial, which is funded by the U.S. National Institutes of Health, using phages grown the traditional way to attack bacterial populations in the lungs of patients. But Schooley can envision using the phactory approach in the future. "There is still so much to learn about phages," he says. "This [new] technique enables us not just to optimize their use but also to study if changes [we introduce] actually have the effects we hypothesized."

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