Research team identifies new approach to fight bacterial infections

Researchers at the Icahn School of Medicine at Mount Sinai have identified a new approach to controlling bacterial infections. The results are described in Nature Structural and molecular biology.

The team found a way to activate 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 some bacteria to protect themselves from viral attacks. The bacteria self-destruct to prevent the spread of the virus to other bacterial cells in the population.

“We wanted to see how the bacterial self-destructive CBASS system is activated and whether it can be exploited to limit bacterial infections,” says co-senior author Aneel Aggarwal, Ph.D., professor of pharmacological sciences at Icahn Mount Sinai. “This is a new approach to combating bacterial infections, a major concern in hospitals and other settings. It is essential to find new tools to combat antibiotic resistance. In the war against superbugs, we must constantly innovate and expand our toolbox to stay ahead of the curve. evolving drug resistance.

According to a 2019 report from the Centers for Disease Control and Prevention, more than 2.8 million antimicrobial-resistant infections occur in the United States each year, resulting in the deaths of more than 35,000 people.

In the experiments, the researchers studied how Cap5, or CBASS-associated protein 5, is activated for DNA degradation and how it could be used to control bacterial infections through a combination of structural analysis and various biophysical, biochemical and cellular tests. Cap5 is a key protein that is activated by cyclic nucleotides (small signaling molecules) to destroy the bacterial cell’s own DNA.

“In our study, we began by identifying which of the many cyclic nucleotides could activate the Cap5 effector of the CBASS system,” says co-senior author Olga Rechkoblit, Ph.D., assistant professor of pharmacological sciences at Icahn Mount Sinai.

“Once we understood this, we took a close look at the structure of Cap5 when bound to these small signaling molecules. Then, with the expert help of Daniela Sciaky, Ph.D., a researcher at Icahn Mount Sinai, we showed that by adding these special molecules into the bacteria’s environment, these molecules could potentially be used to eliminate the bacteria.

The researchers found that determining the structure of Cap5 with cyclic nucleotides was technically challenging, requiring expert help from Dale F. Kreitler, Ph.D., AMX Beamline scientist at Brookhaven National Laboratory. They achieved this using micro-focused synchrotron X-ray radiation in the same facility. Microfocused synchrotron X-ray is a type of X-ray that is not only produced using a specific type of particle accelerator (synchrotron), but is also carefully focused or a more detailed analysis.

Next, the researchers will explore how their findings apply to other types of bacteria and evaluate whether their method can be used to manage infections caused by various harmful bacteria.

Other authors who contributed to this work are Angeliki Buku, Ph.D., and Jithesh Kottur, Ph.D., both of Icahn Mount Sinai.