Engineering viruses to kill deadly pathogens

Northwestern University researchers have successfully coaxed a deadly pathogen to destroy itself from the inside out.

In the new study, researchers modified DNA from a bacteriophage or “phage,” a type of virus that infects and replicates inside of bacteria. Then, the research team put the DNA inside Pseudomonas aeruginosa (P. aeruginosa), a deadly bacterium that is also highly resistant to antibiotics. Once inside the bacterium, the DNA bypassed the pathogen’s defense mechanisms to assemble into virions, which sliced through the bacterium’s cell to kill it.

Building on a growing interest in “phage therapies,” the experimental work represents a critical step toward engineering designer viruses as new therapeutics to kill antibiotic-resistant bacteria. It also reveals vital information about the innerworkings of phages, a little-studied area of biology.

The study was published today (Jan. 24) in the journal Microbiology Spectrum.

“Antimicrobial resistance is sometimes referred to as the ‘silent pandemic,’” said Northwestern’s Erica Hartmann, who led the work. “The numbers of infections and deaths from infections are increasing worldwide. It’s a massive problem. Phage therapy has emerged as an untapped alternative to our reliance on using antimicrobials. But, in many ways, phages are microbiology’s ‘final frontier.’ We don’t know much about them. The more we can learn about how phage work, the more likely we can engineer more effective therapeutics. Our project is cutting-edge in that we are learning about phage biology in real time as we engineer them.”

An indoor microbiologist, Hartmann is an associate professor of civil and environmental engineering at Northwestern’s McCormick School of Engineering and a member of the Center for Synthetic Biology.

Desperate need for antibiotic alternatives

Associated with an increase in antimicrobial use, the rise of antibacterial resistance is an urgent and growing threat to the global population. According to the Centers for Disease Control and Prevention (CDC), nearly 3 million antimicrobial-resistant infections occur each year in the United States alone, with more than 35,000 people dying as a result.

The growing crisis has motivated researchers to look for alternatives to antibiotics, which are continually losing effectiveness. In recent years, researchers have started to explore phage therapies. But even though billions of phages exist, scientists know very little about them.

“For every bacterium that exists, there are dozens of phages,” Hartmann said. “So, there is an astronomically large number of phages on Earth, but we only understand a handful of them. We haven’t necessarily had the motivation to really study them. Now, the motivation is there, and we are increasing the number of tools we have to dedicate to their study.”

Treatment without side effects

To explore potential phage therapies, researchers either pinpoint or modify an existing virus to selectively target a bacterial infection without disrupting the rest of the body. Ideally, scientists one day could tailor a phage therapeutic to infect a specific bacterium and design “a la carte” therapeutics with precise traits and characteristics to treat individual infections.

“What’s powerful about phage is it can be very specific in the way that antibiotics are not,” Hartmann said. “If you take an antibiotic for a sinus infection, for example, it disrupts your entire gastrointestinal tract. A phage therapy can be designed to affect only the infection.”