Researchers discover weakness in bacterial machinery that causes antibiotic resistance

Superbugs are bacteria that are immune to multiple antibiotics and pose a major challenge to modern medicine. Researchers from B CUBE (Centre for Molecular Biotechnology) at the TUD Dresden University of Technology and the Institut Pasteur in Paris have identified a weakness in the bacterial machinery. antibiotic resistance Adaptation. Their findings were published in the journal scientific progress, It could pave the way for increasing the effectiveness of existing antibiotics.

Since the discovery of penicillin in 1928, antibiotics have changed medicine and made it easier to fight bacterial infections. But with the invention of antibiotics, we also entered a never-ending arms race with bacteria. They rapidly adapt to drugs and defeat many existing treatments. These antibiotic-resistant bacteria are often referred to as “superbugs” and pose a serious threat to patients with chronic illnesses or weakened immune systems.

Rather than develop new antibiotics, we wanted to understand exactly how bacteria adapt resistance. ”

Professor Michael Schlierf, B CUBE Research Leader, Research Group Leader, Dresden University of Technology

In doing so, the research group discovered why some bacteria take a long time to develop antibiotic resistance, while others adapt very quickly. Their findings open new possibilities for the development of counterstrategies.

Genetic toolbox in action

“Our research focuses on the integron system, a genetic toolbox that bacteria use to adapt to their environments by exchanging genes, such as for antibiotic resistance,” says the group, who collaborated on the study. Professor Didier Maazel, research group leader at the Pasteur Institute in Paris, said: With the Shrief team.

The Integron System is like a toolbox. This allows bacteria to conserve and share resistance genes with their descendants and neighboring cells. It works through a molecular “cut and paste” mechanism driven by special proteins known as recombinases. Much research has been done on the integron system. Some bacteria acquire new resistance very quickly, while others take much longer.

It turns out that DNA sequence diversity is central to this difference. “Sequences within the integron system are flanked by special DNA hairpins. These are so called because they look just like little U-shaped pins sticking out of the DNA. Recombinases are It is constructed to attach to these hairpins, forming a complex that allows you to cut out one piece and paste another,” Professor Maazel explains.

The Schlierf group used state-of-the-art microscopy equipment to study how tightly recombinase proteins bind to different DNA hairpin sequences. They found that the complexes with the strongest binding between protein and DNA were also the complexes most efficient at acquiring resistance genes.

use force

The Shuliev research group used an advanced microscopy technique known as optical tweezers to measure the small forces it takes to pull apart various protein-DNA complexes. Scientist Dr. Ekaterina Vorobevskaya said: “With optical tweezers, you use light to grab a single strand of DNA from both sides and pull it apart. Think of it like pulling a string to untie a knot. Please,” he says. in the Schleif laboratory, where the project was carried out.

The research group found a clear correlation between the force required to break down protein-DNA complexes and the efficiency of cut-and-paste machines. “If you have a complex that is tightly bound to the DNA, it works really well. You can cut the DNA and stick a new resistance gene on very quickly. Whereas the protein-DNA complex If there is, it becomes weak and keeps falling apart, so it has to be reassembled again and again, which is why some bacteria acquire antibiotic resistance faster than others,” Dr. Borobevskaya added. Ta.

exploit a weakness

“The integron system has been studied by microbiologists for decades. What we now bring to the table is to add biophysical data and explain the behavior of this system in a physical way. “Perhaps this vulnerability to forces is a more general phenomenon for different efficiencies in biology.''

Scientists believe they can exploit weaknesses in this system to develop complementary treatments that harness or generate unstable DNA-protein complexes. When used in conjunction with existing antibiotics, it may provide an additional temporal advantage over bacteria.