Flipping the Switch on Retrons to Fight Antimicrobial Resistance

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In this interview, we talk to Dr. Jacob Bobonis about his new discovery regarding retrons and how they could be used to fight antimicrobial resistance.

Could you introduce yourself and tell us what inspired your latest research on retrons?

My name is Jacob Bobonis and the focus of my PhD in the laboratory of Dr. Nassos Typas at the European Molecular Biology Laboratory (EMBL) in Heidelberg was to discover the biological function of a mysterious group of bacterial genetic elements called retrons.

What are retrons and what characteristics make them difficult to study?

Retrons were discovered in the 1980s in bacteria due to their ability to produce massive amounts of small single-stranded DNA in vivo. Early work showed how this small DNA, called multicopy single-stranded DNA (msDNA), is generated by dedicated reverse transcriptases and retron-encoded small RNAs, but the function of msDNA and retrons has remained a mystery for almost four decades.

The major challenge in finding their function was that retrons seemed non-essential for bacteria, but as so often happens, people were looking in the wrong place.

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In your latest research, you discovered a new feature of retrons. Can you tell us more about how you conducted your study and what you found?

Our study details the discovery of how a retron affects the fitness of a pathogen (Salmonella) and how we used this phenotype to discover that retrons are growth-inhibitory switches that use their msDNA to detect the presence of viruses (phages).

We have shown that retrons contain toxins, which are usually kept inactive by both reverse transcriptase and msDNA, but that specific phage proteins can directly activate these retrotoxins, which then inhibit the growth of Salmonella. This self-targeting toxicity renders the phage-infected bacterium unable to produce more phages, thereby protecting the bacterial population from viral catastrophe.

Retron Switch

Image Credit: Creative Team/EMBL

What implications might your research have for the field of immunology? How might using these switches help treat bacterial infections?

Contrary to common knowledge, our research indicates the existence of a highly specialized and elegant prokaryotic antiviral immune system. Bacteria have hundreds of growth-inhibiting switches that work like retrons, collectively called toxin-antitoxin systems, but for decades researchers couldn’t find what turns them on.

We discovered the first of these trigger mechanisms for retrons and found that they detect epigenetic signals from phages using their mDNA. This suggests that toxin-antitoxin systems detect highly specific virus signals, which, if understood, can be exploited in multiple creative ways as a novel way to inhibit pathogen growth by activating these internal switches of growth inhibition. By designing an approach to find how retrons are activated, we provide a tool that can be used to find what activates one of thousands of other toxin-antitoxin systems.

Antimicrobial resistance

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With antimicrobial resistance being one of the top 10 global public health threats facing humanity, do you hope your discovery can help us better understand antimicrobial resistance? What would this mean for global health?

Our research will be invaluable in arriving at alternative treatment options to antibiotics. Finding out how toxin-antitoxin systems are activated can lead to the development of artificially engineered trigger molecules that enter a pathogen and inhibit its growth in vivo. On the other hand, phages themselves can (and are already beginning) to be used in clinics to counter bacterial infections.

We found that phages carry their own weapons against retrons and built a roadmap on how other researchers can find phage weapons against other toxin-antitoxin systems. This knowledge may lead to the design of decorated phages equipped with sufficient counter-mechanisms to defeat the immune system of bacterial pathogens and eliminate potential infections.

In investigating these “switches”, you have combined the disciplines of genetics, bioinformatics and proteomics. What are the advantages of having a multidisciplinary approach when making new scientific discoveries?

Scientific endeavors are inherently difficult, and often one approach quickly leads to a dead end. The privilege of using multiple approaches allowed us to avoid such dead ends and thus solve the next step of the puzzle.

Bioinformatics is a relatively new scientific discipline, combining both biology and computer science. What advantages does this have for research? Do you believe that as the life sciences industry continues to evolve, we will see more researchers using bioinformatics tools in their studies?

Today, not using bioinformatics tools is a major setback for any science project in biology, and this distinction will certainly deepen over time. The major advantage is that, just like having a multidisciplinary approach to exploring problems, computational biology provides insights that can directly guide us to crucial experiments.

Bioinformatics

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Your research team was a collaborative effort made up of different researchers from different institutions. How important was the collaboration to your research and the science sector as a whole?

The collaboration between (at least) seven different laboratories from two continents has been key to the success of our research efforts. Perhaps equally important, working with motivated collaborators makes the scientific process more enjoyable, more creative and more human.

What’s next for you and your research?

I will soon start working as a postdoctoral fellow at the University of Vienna in the laboratory of Dr. Martin Polz to explore the molecular intricacies of phage-bacteria interactions in the oceans.

Where can readers find more information?

About Dr. Jacob Bobonis

Postdoctoral researcher at the University of Vienna studying phage-bacteria interactions.

PhD from the European Molecular Biology Laboratory (EMBL) in Heidelberg.Dr. Jacob Bobonis

Received the 2021 Nat L. Sternberg Dissertation Award for Outstanding Ph.D. work in bacterial molecular biology.

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