3-D structure: how phages work and how they are built

Phages at work: artist’s impression of phages (green and yellow) attacking a bacterium (blue).

Phages have become the focus of research in the fight against antibiotic resistance. The bacteria-eating viruses have already proven effective against multi-resistant bacteria in experiments. However, it is unknown how the little helpers are structured at the atomic level.

Researchers from the Leibniz Research Institute for Molecular Pharmacology (FMP) in Berlin have now been able to develop a new method that can be used to elucidate the complex structure down to atomic detail. The work is based on a further development of solid-state NMR and has been published in the journals Applied chemistry [1] and Nature Protocols [2] published.

WHO: global health crisis

The WHO has long since declared antibiotic resistance a global health crisis, and most recently in March published a list of problem germs for which new antibiotics are needed most urgently. But the search for new antibiotics is proving difficult: There has been no significant progress in development for more than 40 years.

Specific phages against specific bacteria

Researchers are therefore increasingly looking for therapeutic alternatives. Phages could represent such an alternative. These are naturally occurring viruses that attack and eat certain bacteria and are therefore called "bacteriophages" (ancient Greek φαγεῖν phageIn "to eat").

Since there are specific phages for each bacterium, they appear to be even more targeted than antibiotics, which always kill "good" bacteria as well. There has already been a lot of experimentation with bacteriophages in Eastern Europe, and in the US they are now being genetically engineered to be able to cure mice of infections with multidrug-resistant germs.

Nanomachines optimized over millions of years

The exact structure of phages is not yet completely known. In the course of the current therapy development, it would be enormously important to know how exactly they operate and what their 3-D structure looks like in atomic detail.

"Phages are nanomachines optimized by nature over millions of years. They are made up of many components that come together to form a complex architecture," explains Prof. Dr. Adam Lange from the Leibniz Research Institute for Molecular Pharmacology (FMP). Lange and his team have now achieved a methodological milestone: The researchers have further developed solid-state NMR (nuclear magnetic resonance spectroscopy) methods in such a way that they can be used to elucidate the structure of phages down to atomic detail.

Lange estimates that it will take him about a year to elucidate the complex structure of phages. "This will allow us to make an important contribution to phage therapy in the context of basic research."

Making protein structures visible

The new method can be applied to other important systems as well. So that laboratories all over the world can make use of it, the researchers have, in addition to the work in Applied chemistry [1] a detailed protocol in Nature Protocols [2] published.
"Bacteriophages are becoming increasingly important as an alternative therapeutic approach due to the antibiotic resistance of many pathogenic bacterial strains," concludes Lange, who is a leader in the field of NMR-based visualization of protein structures. "That’s why we’re now going to use our technical advancement to clear up their complex structure as quickly as possible."

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