Scientists at the Gladstone Institutes in the United States have developed a technology that enables them to modify viruses that attack bacteria in a very simple and effective way, giving them the ability to engineer new viruses and study how to benefit from these viruses to target and eliminate specific bacteria, in an attempt to search for a new mechanism to solve the problem of antibiotic-resistant bacteria.
Searching for an alternative to antibiotics
Bacteriophages, or bacteriophages, are viruses that naturally target and kill bacteria. Although there are thousands of these viruses, using phages as therapeutics to combat specific types of bacteria has proven challenging. To improve phage therapy and make it scalable to treat human diseases, scientists need ways to modify them and turn them into efficient bacteria-killing machines. This approach could provide an alternative to treating bacterial infections that are resistant to traditional antibiotics.
“Ultimately, if we want to use phages to save the lives of people with multidrug-resistant infections, we need a way to make and test many versions of phages to find the best ones,” says Seth Shipman, PhD, a Gladstone research associate and lead author of the study published in Nature Biotechnology on September 5. “This new technology allows us to quickly and successfully make different modifications to the phage genomes so that we can create many versions.”
DNA Factory
The new method relies on molecules called retrons, which originate from bacterial immune systems and act as DNA-producing factories inside bacterial cells. Shipman’s team has found ways to program retrons to produce copies of the desired DNA sequence. When phages infect a bacterial colony containing retrons, using the technique described in the new study, the phages incorporate the DNA sequence produced by the retrons into their own genomes.
Shipman’s group wanted to find a way to modify their phage genomes to create large collections of phages that could be screened for therapeutic use, as well as to collect data on what makes some phages more effective or more or less specific for bacterial targets.
“Bacteriophages play an important role in shaping microbial communities as natural predators of bacteria,” says Chloe Fishman, a former Gladstone researcher and co-first author of the new study who is now a graduate student at Rockefeller University. “It’s important that we have tools to modify their genomes to better study them. It’s also important if we want to engineer them so that we can shape microbial communities to our advantage, for example, to kill antibiotic-resistant bacteria.”
Shipman and his colleagues began by creating retrons that produce DNA sequences specifically designed to modify phages, a system the team called “recombination.” They then placed these retrons in colonies of bacteria. Finally, they let the phages infect these bacterial colonies. As the phages infected one bacteria after another, they acquired and incorporated the new DNA from the retrons, modifying their genomes.
The research team showed that the longer the phages infect a bacterial colony containing retrons, the more of the phage genomes are modified. Furthermore, the researchers were able to program different bacteria within the colony with different retrons, allowing the phages to acquire multiple modifications as they infect the colony.
“When phages move from one bacterium to another, they acquire different modifications,” Shipman says, according to EurekAlert. “Multiple modifications in phages used to be so difficult that scientists didn’t do it very often. Now, you can simply drop some phages into these cultured bacteria, wait a while, and get multiple modified phages.”
Enemy of your enemy
Unlike antibiotics, which kill many types of bacteria at once, phages are highly specific to specific types of bacteria. With the rising incidence of antibiotic-resistant bacterial infections, estimated at 2.8 million in the United States each year, researchers are increasingly looking at the potential of phage therapy as an alternative to combat these infections.
“They say your enemy’s enemy is your friend,” says Shipman, who is also an associate professor in the Department of Bioengineering and Therapeutic Sciences at UC San Francisco and a Chan Zuckerberg Institute researcher. “Our enemies are these pathogenic bacteria, and their enemies are phages.”