A team of researchers has discovered a method to activate a bacterial defense system, known as CBASS, to self-destruct and prevent the spread of viruses among bacteria, potentially offering a new way to manage bacterial infections and combat antibiotic resistance. Credit: SciTechDaily.com
Researchers unveil how the self-killing activity of bacteria can be harnessed in the fight against antibiotic resistance.
Scientists at the Icahn School of Medicine at Mount Sinai have identified a new approach to controlling bacterial infections. The findings were described in the February 6 online issue of Nature Structural & Molecular Biology<em>Nature Structural & Molecular Biology</em> is a scientific journal that publishes research articles in the fields of structural biology and molecular biology. Structural biology is the study of the three-dimensional structures of biological molecules, including proteins, nucleic acids, and carbohydrates, and how they function in cells. Molecular biology is the study of the processes that occur within cells at the molecular level, including the regulation of gene expression and the structure and function of cellular components such as enzymes and membranes.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Nature Structural & Molecular Biology.
The team found a way to turn on a vital bacterial defense mechanism to fight and manage bacterial infections. The defense system, called cyclic oligonucleotide-based antiphage signaling system (CBASS), is a natural mechanism used by certain bacteria to protect themselves from viral attacks. Bacteria self-destruct as a means to prevent the spread of virusA virus is a tiny infectious agent that is not considered a living organism. It consists of genetic material, either DNA or RNA, that is surrounded by a protein coat called a capsid. Some viruses also have an outer envelope made up of lipids that surrounds the capsid. Viruses can infect a wide range of organisms, including humans, animals, plants, and even bacteria. They rely on host cells to replicate and multiply, hijacking the cell's machinery to make copies of themselves. This process can cause damage to the host cell and lead to various diseases, ranging from mild to severe. Common viral infections include the flu, colds, HIV, and COVID-19. Vaccines and antiviral medications can help prevent and treat viral infections.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>virus to other bacterial cells in the population.
CBASS Defense Mechanism Explored
“We wanted to see how the bacterial self-killing CBASS system is activated and whether it can be leveraged to limit bacterial infections,” says co-senior author Aneel Aggarwal, PhD, Professor of Pharmacological Sciences at Icahn Mount Sinai. “This is a fresh approach to tackling bacterial infections, a significant concern in hospitals and other settings. It’s essential to find new tools for fighting antibiotic resistance. In the war against superbugs, we need to constantly innovate and expand our toolkit to stay ahead of evolving drug resistance.”
According to a 2019 report by the Centers for Disease Control and Prevention, more than 2.8 million antimicrobial-resistant infections occur in the United States each year, with over 35,000 people dying as a result.
Icahn Mount Sinai researchers unveil how the self-killing activity of bacteria can be used in the fight against antibiotic resistance. Above: 3-D structure of CBASS Cap5 protein tetramer (shown in cyan) formed upon binding to the cyclic dinucleotide (shown in orange) to destroy bacteria’s own DNA (model, shown in red). Essential magnesium ions for DNA cleavage are shown in green. Credit: Rechkoblit et al., Nature Structural & Molecular Biology
Innovative Strategies Against Superbugs
As part of the experiments, the researchers studied how “Cap5,” or CBASS-associated protein 5, is activated for DNADNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>DNA degradation and how it could be used to control bacterial infections through a combination of structural analysis and various biophysical, biochemical, and cellular assays. Cap5 is a key protein that becomes activated by cyclic nucleotides (small signaling molecules) to destroy the bacterial cell’s own DNA.
“In our study, we started by identifying which of the many cyclic nucleotides could activate the effector Cap5 of the CBASS system,” says co-senior author Olga Rechkoblit, PhD, Assistant Professor of Pharmacological Sciences at Icahn Mount Sinai. “Once we figured that out, we looked closely at the structure of Cap5 when it’s bound to these small signaling molecules. Then, with expert help from Daniela Sciaky, PhD, a researcher at Icahn Mount Sinai, we showed that by adding these special molecules to the bacteria’s environment, these molecules could potentially be used to eliminate the bacteria.”
Overcoming Technical Challenges
The researchers found that determining the structure of Cap5 with cyclic nucleotides posed a technical challenge, requiring expert help from Dale F. Kreitler, PhD, AMX Beamline Scientist at Brookhaven National Laboratory. It was achieved by using micro-focused synchrotron X-ray radiation at the same facility. Micro-focused synchrotron X-ray radiation is a type of X-ray radiation that is not only produced using a specific type of particle accelerator (synchrotron) but is also carefully concentrated or focused on a tiny area for more detailed imaging or analysis.
Future Directions
Next, the researchers will explore how their discoveries apply to other types of bacteria and assess whether their method can be used to manage infections caused by various harmful bacteria.
Reference: “Activation of CBASS-Cap5 endonuclease immune effector by cyclic nucleotides” 6 February 2024, Nature Structural & Molecular Biology.
DOI: 10.1038/s41594-024-01220-x
Other authors who contributed to this work are Angeliki Buku, PhD, and Jithesh Kottur, PhD, both with Icahn Mount Sinai.
The work was funded by National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>National Institutes of Health grants R35-GM131780, P41GM111244, KP1605010, P30 GM124165, S10OD021527, GM103310, and by the Simons Foundation grant SF349247.
Source: SciTechDaily
