'Antibiotic resistance is one of the top health threats'

Newly discovered RNA molecule could lead to new treatments in war against ‘superbugs’

As antibiotic-resistant bacteria threaten global health, Hebrew University scientists use innovative method to discover PreS, a ‘secret switch’ that boosts bacteria-eating viruses

Researchers from the Hebrew University of Jerusalem have discovered a tiny RNA molecule that can potentially lead the way toward treatments against antibiotic-resistant bacteria.

Called PreS, the molecule enables a bacteria-eating virus known as a bacteriophage — or phage, for short — to take control of a bacterial cell and use it for its own growth, eventually destroying the bacterium.

“Antibiotic resistance is one of the most serious global health threats of our time,” Dr. Sahar Melamed, head of the Hebrew University of Jerusalem’s Melamed lab, told The Times of Israel.

Understanding how phages operate can “aid scientists in furthering research and therapies that might help fight antibiotic-resistant bacteria,” he said.

The peer-reviewed study, led by PhD student Aviezer Silverman, MSc student Raneem Nashef, and computational biologist Reut Wasserman from the Hebrew University, in collaboration with Prof. Ido Golding’s group from the University of Illinois Urbana-Champaign, appeared on Thursday in the journal Molecular Cell.

The global threat of antibiotic-resistant bacteria

The rise of antimicrobial resistance has become a global health challenge.

Around the world, these bacteria that defy antibiotics — commonly known as “superbugs” — were directly responsible for 1.27 million global deaths in 2019, according to the World Health Organization.

As early as 2013, a State Comptroller’s report found that some 5,000 Israelis were dying annually from infections associated with this bacterial resistance, and those numbers continue to rise.

A French-Canadian microbiologist, Félix d’Hérelle, first discovered bacteriophages in 1917. He chose the name from the Ancient Greek phagein, to devour, or to eat bacteria. He found the bacteriophage that destroyed the bacteria that cause dysentery.

Once penicillin was discovered, most scientists stopped researching phages. As bacteria have become more resistant to antibiotics, researchers realized they needed more solutions and returned to phage research.

Phage therapy research in Israel

The need for a solution has become increasingly urgent as more bacteria become resistant to antibiotic treatment. Over the course of the two-year war in Gaza, dozens of IDF soldiers became infected with these superbugs. One soldier, Hanan Drori, died from a severe fungal infection.

In 2018, the Israel Phage Therapy Center was established in partnership with Hadassah Medical Center, focusing on the therapeutic potential of phages that target and kill bacteria with precision, with numerous successful phage treatments against microbial infections.

Since the war began, the center’s researchers have named some of the phages that they discover in memory of people who were killed.

Listening to RNAs ‘talk’ to each other

Melamed said the lab used RIL-seq (RNA Interaction by Ligation and sequencing), a method he developed during his post-doctorate studies in Prof. Hanah Margalit’s lab at Hebrew University.

The scientist said that he invented a new application for RIL-seq in this current study to map interactions “while the bacteria are infected with the phage,” Melamed explained.

RIL-seq is a method that identifies interacting RNA molecules inside a cell by “gluing” them together and then sequencing the joined molecules to see which RNAs are paired.

The researchers could study how small RNAs “talked” to each other within the bacteria, uncovering “a new level of communication between bacteria and phages,” he said, mapping RNA interactions that were previously hard to see.

Melamed said they were surprised to discover the tiny RNA molecule PreS inside a lambda phage, which attacks E. coli bacteria.

“[Lambda] is one of the most studied viruses for the past 75 years,” he said, “but we found PreS, which no one had noticed before.”

“PreS hijacks the bacterium’s replication machinery,” Melamed said.

It is then able to “reproduce efficiently inside individual bacteria,” he explained. “It also maximizes its spread through the bacterial population.”

As an increasing number of phages are produced, they get so numerous that they burst out of the cell, killing the bacterium.

Uncovering how PreS takes control of bacterial cells provides important basic knowledge that could help scientists design smarter, more effective phage treatments in the future.

Melamed said his lab’s next study will focus on finding other RNA molecules in diverse phages, “to understand how they also manipulate bacterial systems and tailor them for their needs.”

“Scientists are actively seeking alternative treatments for antimicrobial resistance,” Melamed said. “One particularly promising approach is phage therapy, which uses viruses that specifically infect and kill bacteria, offering a targeted and potentially powerful alternative to conventional antibiotics.”

He added that this research changes “how we think about the molecular dialogue between phages and their hosts, providing potential new routes for phage therapy.”