Superbugs, bacteria that are immune to multiple antibiotics, pose a great challenge to modern medicine. Researchers from the B CUBE - Center for Molecular Bioengineering at TUD Dresden University of Technology and Institut Pasteur in Paris identified a weakness in the bacterial machinery that drives antibiotic resistance adaptation. Their findings, published in the journal Science Advances, could pave the way to boosting the effectiveness of existing antibiotics.
Since the discovery of penicillin in 1928, antibiotics have changed medicine, allowing us to easily combat bacterial infections. However, with the invention of antibiotics, we have also entered a never-ending arms race with bacteria. They adapt rapidly to drugs, rendering many existing treatments ineffective. Such antibiotic-resistant bacteria, often dubbed "superbugs", pose a critical threat to patients with chronic illnesses and weakened immune systems.
"Rather than developing new antibiotics, we wanted to understand exactly how bacteria adapt their resistances," says Prof. Michael Schlierf, research group leader at B CUBE, TU Dresden, the leader of the study. In doing so, the groups discovered why it takes longer for some bacteria to develop antibiotic resistance, while others adapt very quickly. Their findings open up new possibilities for the development of 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," says Prof. Didier Mazel, research group leader at Institut Pasteur in Paris, whose group worked together with the Schlierf team.
The integron system is like a toolbox. It allows bacteria to store and share resistance genes with their offspring and neighboring cells. It operates via a molecular "cut and paste" mechanism driven by special proteins, known as recombinases. The integron system has been researched a lot. Some bacteria gain new resistance very fast and for others, it takes considerably longer.
It turned out that the variety of DNA sequences is at the heart of this difference. "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," explains Prof. Mazel.
The Schlierf group used a cutting-edge microscopy setup to study how strongly a recombinase protein binds the different DNA hairpin sequences. They found that the complexes with the strongest binding between the protein and the DNA are also the ones that are the most efficient at gaining resistance genes.
Using the Force
Using an advanced microscopy technique known as optical tweezers, the Schlierf group measured the tiny forces it takes to pull the different protein-DNA complexes apart. "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," says Dr. Ekaterina Vorobevskaia, a scientist in the Schlierf lab who carried out the project.
The group saw a clear correlation between the force it took to dismantle a protein-DNA complex and the efficiency of the cut-and-paste machinery. "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," adds Dr. Vorobevskaia.
Exploiting the Weakness
"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," says Prof. Schlierf, adding that "Maybe this vulnerability to force is a more general phenomena for varying efficiencies in biology".
The scientists believe that the weakness in the system can be used to develop supplemental treatments that will take advantage of, or create, the unstable DNA-protein complexes. It could accompany existing antibiotics and give them an additional time advantage over bacteria.
About the B CUBE - Center for Molecular Bioengineering
B CUBE – Center for Molecular Bioengineering was founded as a Center for Innovation Competence within the initiative "Unternehmen Region" of the German Federal Ministry of Education and Research. It is part of the Center for Molecular and Cellular Bioengineering (CMCB). B CUBE research focuses on the investigation of living structures on a molecular level, translating the ensuing knowledge into innovative methods, materials and technologies.
Web: http://www.tu-dresden.de/cmcb/bcube
About Institute Pasteur
The Institut Pasteur, a non-profit foundation with recognized charitable status set up by Louis Pasteur in 1887, is today an internationally renowned center for biomedical research. In the pursuit of its mission to tackle diseases in France and throughout the world, the Institut Pasteur operates in four main areas: research, public health, training, and development of research applications. The Institut Pasteur is a globally recognized leader in infectious diseases, microbiology, and immunology, with research focusing on the biology of living systems. Among its areas of investigation are emerging infectious diseases, antimicrobial resistance, certain cancers, neurodegenerative diseases, and brain connectivity disorders. The Institut Pasteur's outstanding research is facilitated by the development of a technological environment of the highest standard, with core facilities for nanoimaging, computational biology and artificial intelligence. Since its inception, 10 Institut Pasteur scientists have been awarded the Nobel Prize for Medicine, including two in 2008 for the 1983 discovery of the human immunodeficiency virus (HIV) that causes AIDS.
The Institut Pasteur is part of the Pasteur Network a worldwide network of 33 members on five continents, united by Pasteurian values, that contribute to global health.
Since July 1, 2021, the Institut Pasteur is a research partner organization of Université Paris Cité.
Web: www.pasteur.fr/en
