The idea of using viruses to kill disease-causing bacteria is not new. But fine-tuning them to attack specific bacteria is time-consuming and expensive. Now, biological engineers have devised a system that makes it much easier to tweak the genomes of bacteria-eating viruses to target specific pathogens.

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The new system customizes phages (shown in yellow) to selectively attack specific bacteria.
Image credit: Christine Daniloff/MIT

At the heart of the "mix-and-match" system is a standardized genetic scaffold of a bacteriophage - a virus that "eats" bacteria. The idea is that by swapping genes in and out of the scaffold, scientists will be able to custom-build phages to target any type of pathogenic bacteria.

The new system is the creation of a team from Massachusetts Institute of Technology (MIT) and features in a paper published in the journal Cell Systems.

Senior author Timothy Lu, an associate professor of electrical engineering and computer science and biological engineering, says:

"These bacteriophages are designed in a way that's relatively modular. You can take genes and swap them in and out and get a functional phage that has new properties."

He and his colleagues hope the system will help make phages that kill bacteria for which there are no effective antibiotics.

They also see it being useful in other areas - for example, to "edit" mixed populations of bacteria, such as those found in the gut. The human digestive tract is home to trillions of bacterial cells. Some of the species in this gut microbiome are friendly and help digestion, but others cause disease.

Hitting the gut with antibiotics to kill the bad bacteria would also kill the friendly ones. There is a need for a tool that goes in and selectively kills only the bad ones.

"Antibiotics can kill off a lot of the good flora in your gut," Prof. Lu explains. "We aim to create effective and narrow-spectrum methods for targeting pathogens."

Prof. Lu says first they plan to remove certain members of the bacterial colonies to see what role they play in the gut microbiome. Then:

"In the longer term you could design a specific phage that kills that bug but doesn't kill the other ones, but more information about the microbiome is needed to effectively design such therapies."

Standardized genetic scaffold for customizing phages more quickly

Many bacteriophages are made of a head region attached to a tail that latches onto the target. For their study, the team began with a family of phages known as T7. These naturally attack Escherichia coli. By swapping genes in the tail, they created phages that target several types of bacteria.

"You keep the majority of the phage the same and all you're changing is the tail region, which dictates what its target is," says Prof. Lu.

So far, the only phages approved by the Food and Drug Administration (FDA) have been for treating food products. For example, FDA-approved purified phages can be used as an antimicrobial additive in ready-to-eat meat and poultry products to protect against Listeria.

Isolating naturally-occurring phages suitable for medical use from sewage and soil is tedious and time-consuming. Also, because the different types have varied genome organizations and life cycles, they pose a challenge for regulatory approval and clinical use.

By devising a standardized genetic scaffold for their phages, the MIT team believes they have created a more streamlined process, where you only need to swap a few genes to fine-tune the phages to seek out different targets.

The researchers searched databases of phage genomes to find sequences that code for the tail of T7, which is known as gp17. Once they found them, they then devised a new way to genetically engineer the T7 genome to make the swapping less laborious.

They found that inserting the viral genome into a yeast cell - where it sits like an "artificial chromosome" alongside the yeast's own genome - makes it more accessible for gene-swapping, as Prof. Lu explains:

"Once we had that method, it allowed us very easily to identify the genes that code for the tails and engineer them or swap them in and out from other phages. You can use the same engineering strategy over and over, so that simplifies that workflow in the lab."

In the study, the MIT team showed they could engineer phages that target strains of Gram-negative bacteria, including Yersinia, Klebsiella and E. coli.

There are few new antibiotics against Gram-negative bacteria, which include microbes that cause many human respiratory, urinary, and gastrointestinal conditions, such as pneumonia, gastritis, sepsis and Legionnaires' disease.

'A big step in the development of phage therapies'

The new mix-and-match system also overcomes another difficulty with using phages to treat disease. Phages tend to infect a limited number of bacterial strains, so finding the right ones for specific diseases takes time, and even then they may not exist.

David Bikard, a microbiologist at the Institut Pasteur in Paris, France, who was not involved in the study, comments on the work:

"This is a big step in the development of phage therapies with predictable outcomes and a good demonstration of what synthetic biology approaches will bring to medicine in the near future."

The team also plans to devise phages for other applications such as spraying crops or disinfecting food. As the phages would be based on an identical genetic scaffold, it should greatly speed up the regulatory approval process, Prof. Lu concludes.

The study follows one by another MIT team that Medical News Today reported earlier this year. In that study, the researchers engineered particles called phagemids to enter and kill bacteria without bursting them so they do not release toxins that can produce nasty side effects.