Creating viruses to eliminate harmful germs

Engineering pseudomonas aeruginosa phages using synthetic biology for clinical relevance.

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Northwestern University researchers have successfully programmed a lethal pathogen, Pseudomonas aeruginosa, to self-destruct. In this study, they modified DNA from a bacteriophage (phage), a virus infecting bacteria, and inserted it into P. aeruginosa, a highly antibiotic-resistant bacterium, the modified DNA evaded the pathogen’s defenses and formed virions. 

These virions then cut through the bacterium’s cells, effectively killing it. This breakthrough contributes to developing designer viruses for phage therapies, offering a potential solution to combat antibiotic-resistant bacteria. The study was published in Microbiology Spectrum, shedding light on phages’ inner workings.

Northwestern’s Erica Hartmann, who led the work, said, “Antimicrobial resistance is sometimes called the ‘silent pandemic. The number 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 antimicrobials. But, in many ways, phages are microbiology’s ‘final frontier.’ We don’t know much about them. The more we learn about how phage works, the more likely we can engineer more effective therapeutics. Our project is cutting-edge because we are learning about phage biology in real time as we engineer them.”

Hartmann, an indoor microbiologist at Northwestern, works on antibiotic alternatives due to the escalating threat of antibiotic-resistant infections. With nearly 3 million cases yearly in the U.S. alone, causing over 35,000 deaths, the need for solutions is urgent.

Due to the diminishing effectiveness of antibiotics, researchers seek alternatives. Phage therapies have gained attention by exploring viruses called phages to combat bacteria. Despite the vast number of phages—billions existing—scientists have limited knowledge. According to Hartmann, there’s a considerable motivation to understand them better. The growing crisis prompts increased tools and dedication to study these viruses.

In the quest for treatment with minimal side effects, researchers explore phage therapies. These therapies involve targeting or modifying a virus to specifically attack a bacterial infection without harming the rest of the body. The goal is to tailor phage therapeutics with precise characteristics for individual conditions, offering a specific and practical approach. Phage therapies, unlike antibiotics, can be particular, impacting only the infection without disrupting other bodily functions, presenting a potential breakthrough in personalized and targeted medical treatments.

While most phage therapy research centers on Escherichia coli, Hartmann focused on Pseudomonas aeruginosa, a highly deadly human pathogen. P. aeruginosa poses a significant threat to individuals with weakened immune systems, causing hospital infections, especially in those with burn or surgery wounds and individuals with cystic fibrosis. Given its high drug resistance, developing alternative therapeutics is urgently needed, making P. aeruginosa a critical focus for research.

Hartmann’s team used P. aeruginosa bacteria and phage DNA to simulate infection. They created temporary holes in the bacteria using electroporation, allowing phage DNA to enter and mimic disease. Initially, some bacteria destroyed the foreign DNA to protect themselves.

However, the team successfully turned off the bacteria’s antiviral defenses through synthetic biology optimization. The introduced DNA produced virions that killed the bacteria. This success extended to using DNA from phages that are naturally unable to infect P. aeruginosa, demonstrating the potential of this approach.

The engineered phages not only killed the bacteria but also prompted the bacteria to release billions more phages. These newly generated phages have the potential to combat other bacterial infections. Hartmann’s team is now focusing on studying these expelled phages from P. aeruginosa. This research is a crucial step toward developing phage therapies. 

By analyzing the phages, researchers can choose which ones to develop further and eventually mass-produce for therapeutic use. The study, titled “A synthetic biology approach to assemble and reboot clinically relevant Pseudomonas aeruginosa tailed phages,” received support from the Walder Foundation, the National Science Foundation, and the National Institutes of Health.

Journal reference:

  1. Thomas Ipoutcha, Ratanachat Racharaks, et al., A synthetic biology approach to assemble and reboot clinically relevant Pseudomonas aeruginosa tailed phages. Microbiology Spectrum. DOI: 10.1128/spectrum.02897-23.

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