Superbugs, which are bacteria resistant to many antibiotics, represent a significant hurdle for contemporary healthcare. Recent research has pinpointed a vulnerability in the mechanisms that enable these bacteria to adapt and resist antibiotics.
Superbugs, or bacteria that resist numerous antibiotics, create considerable challenges for modern healthcare. A group of researchers from B CUBE — Center for Molecular Bioengineering at TUD Dresden University of Technology and Institut Pasteur in Paris have discovered a flaw in the bacterial systems that facilitate adaptation to antibiotic resistance. Their research, shared in the journal Science Advances, may lead to enhanced efficacy of current antibiotics.
Since penicillin was discovered in 1928, antibiotics have revolutionized healthcare by making it easier to treat bacterial infections. However, the advent of antibiotics has ignited a continuous struggle between medical science and bacteria, which quickly evolve to outsmart these drugs, leading to many treatments becoming ineffective. These antibiotic-resistant bacteria, commonly referred to as “superbugs,” present a severe risk to individuals who suffer from chronic diseases or have compromised immune systems.
“Instead of creating new antibiotics, we aimed to gain insights into how bacteria develop resistance,” explains Prof. Michael Schlierf, the study’s lead researcher from B CUBE, TU Dresden. This research revealed variances in how swiftly different bacteria develop antibiotic resistance, unveiling avenues for new countermeasures.
A Genetic Toolbox in Action
“Our research centers around the integron system, which acts as a genetic toolbox allowing bacteria to adapt to their surroundings by sharing genes, including those responsible for antibiotic resistance,” states Prof. Didier Mazel, head of the research team at Institut Pasteur in Paris, who collaborated with Schlierf’s group.
The integron system functions like a toolbox, enabling bacteria to store and exchange resistance genes with their progeny and adjacent cells. It relies on a molecular “cut and paste” strategy facilitated by specific proteins known as recombinases. While the integron system has been extensively studied, the rate at which bacteria acquire new resistance can vary significantly.
This variation is largely due to differences in DNA sequences within the integron system. “The DNA sequences are bordered by unique DNA hairpins—named for their U-shaped appearance—that allow recombinases to attach and create a structure capable of cutting and replacing segments of DNA,” details Prof. Mazel.
The Schlierf lab employed cutting-edge microscopy techniques to investigate the strength of a recombinase protein’s binding to various DNA hairpin sequences. Their results indicated that stronger binding complexes between the protein and DNA were more effective in acquiring resistance genes.
Using the Force
Utilizing advanced microscopy known as optical tweezers, the Schlierf team measured the minuscule forces required to separate different protein-DNA pairs. “With optical tweezers, we essentially use light to grasp a single DNA strand from both ends and pull it apart, similar to loosening a knot in a cord,” explains Dr. Ekaterina Vorobevskaia, a scientist from the Schlierf lab involved in the research.
The group observed a direct relationship between the strength needed to disassemble a protein-DNA complex and the effectiveness of the cut-and-paste actions. “A strong protein-DNA complex can efficiently cut the DNA and swiftly insert a new resistance gene. Conversely, weak complexes that frequently fall apart require continuous reassembly, explaining why some bacteria acquire antibiotic resistance more rapidly than others,” Dr. Vorobevskaia comments.
Exploiting the Weakness
“The integron system has long been a focus for microbiologists, but our contribution lies in integrating biophysical data to elucidate the system’s behavior through a physical lens,” says Prof. Schlierf, adding that “this susceptibility to force may reflect a broader principle across various biological systems.”
The researchers believe this identified weakness in the integron system could inform the creation of additional treatments designed to exploit or induce instability in DNA-protein complexes, complementing existing antibiotics and enhancing their efficacy against bacteria.
