New Strategy to Combat Antibiotic-Resistant Bacteria

Modern medicine faces a significant challenge from superbugs, which are bacteria resistant to several antibiotics. Researchers from the B CUBE-Center for Molecular Bioengineering at TUD Dresden University of Technology and Institut Pasteur in Paris discovered a flaw in the bacterial machinery that propels antibiotic resistance adaptation.

Their research, published in the journal Science Advances, may help make current antibiotics more effective.

Antibiotics have revolutionized medicine since the 1928 discovery of penicillin, making it simple to treat bacterial infections. However, since the development of antibiotics, people have also entered a never-ending arms race with bacteria.

They quickly adjust to medications, making many current therapies ineffective. Patients with weakened immune systems and chronic illnesses are particularly vulnerable to these antibiotic-resistant bacteria, frequently called “superbugs.”

Rather than developing new antibiotics, we wanted to understand exactly how bacteria adapt their resistances.”

Michael Schlierf, Research Group Leader, Professor and Study Lead, Technische Universität Dresden

By doing this, the teams learned why some bacteria adapt to antibiotics more slowly while others do so more quickly. Their discoveries create fresh opportunities for counter-strategies.

A Genetic Toolbox in Action

Our work focuses on the integron system, a genetic toolbox that bacteria use to adapt to their environment by exchanging genes, including those for antibiotic resistance.”

Didier Mazel, Professor, Technische Universität Dresden

Mazel is a Research Group Leader at Institut Pasteur in Paris, whose group worked with the Schlierf team.

Integron is similar to a toolbox. It enables bacteria to store and distribute resistance genes to nearby cells and their progeny. It functions through a molecular “cut and paste” process fueled by unique proteins called recombinases. Many studies have been conducted on the integron system. It takes much longer for some bacteria to develop new resistance than for others.

It was discovered that the main cause of this variation is the diversity of DNA sequences.

“The sequences inside the integron system are flanked by special DNA hairpins. They are called like this because this is exactly how they look like, like little U-shaped pins sticking out of the DNA. The recombinases are built to bind to these hairpins and form a complex that can then cut out one fragment and paste in another one,” explained Mazel.

Using a state-of-the-art microscopy setup, the Schlierf group investigated the strength of a recombinase protein's binding to the various DNA hairpin sequences. They discovered that the most effective complexes at acquiring resistance genes also have the strongest protein-DNA binding.

Using the Force

The Schlierf group used optical tweezers, a sophisticated microscopy technique, to measure the minuscule forces required to separate the various protein-DNA complexes.

With the optical tweezers, we use light to, sort of, grab a single strand of DNA from both sides and pull it apart. Think of it as pulling on a cord to undo a knot.”

Dr. Ekaterina Vorobevskaia, Scientist, Technische Universität Dresden

The team observed a direct relationship between the effectiveness of the cut-and-paste equipment and the force required to break up a protein-DNA complex.

“If you have a complex that is strongly bound to the DNA, it can perform its job very well. Cut the DNA and paste a new resistance gene very fast. On the other hand, if you have a protein-DNA complex that is rather weak and keeps falling apart, it has to be reassembled again and again. This is why some bacteria gain antibiotic resistance faster than others,” added Dr. Vorobevskaia.

Exploiting the Weakness

Schlierf said, “The Integron system has been studied by microbiologists for decades. What we bring to the table now is adding the biophysical data and explaining the behavior of this system with physics. Maybe this vulnerability to force is a more general phenomena for varying efficiencies in biology.”

The researchers think the system's flaw can be exploited to create or exploit the unstable DNA-protein complexes to develop additional treatments. These might be used in conjunction with current antibiotics to give them an extra edge over bacteria.