A molecule so small it had escaped notice for seventy-five years
As the age of antibiotics falters under the weight of resistance, a team at Hebrew University of Jerusalem has uncovered a molecular secret hidden for seventy-five years inside one of science's most studied viruses. The discovery of PreS — an RNA switch that enables bacteriophages to commandeer and destroy bacterial cells from within — offers a new foothold in humanity's oldest struggle against infection. With over a million lives lost annually to resistant bacteria, this quiet breakthrough in molecular listening may help restore what modern medicine has slowly been losing.
- Antibiotic-resistant bacteria are killing at a scale that conventional medicine can no longer contain — 1.27 million deaths globally in 2019 alone, and roughly 5,000 Israelis every year.
- A molecule called PreS, hidden inside the lambda phage for seventy-five years, has finally been identified as the biological switch that forces bacteria to destroy themselves from within.
- Researchers at Hebrew University used an RNA-mapping technique called RIL-seq to eavesdrop on molecular conversations between viruses and bacteria, catching PreS in the act of hijacking a cell's own machinery.
- The discovery lands at a moment of renewed urgency for phage therapy — a century-old idea abandoned when penicillin arrived, now racing back as superbugs outpace every antibiotic in the arsenal.
- Understanding PreS opens the door to rationally engineering more precise, harder-to-resist phage treatments, with the research team already planning to search for similar switches across other bacterial viruses.
Antibiotic-resistant bacteria are one of medicine's most pressing crises — responsible for 1.27 million deaths worldwide in 2019 and roughly 5,000 Israeli lives each year. Conventional drugs are losing ground, and the search for alternatives has grown desperate. Into this gap steps a discovery from Hebrew University of Jerusalem: a tiny RNA molecule called PreS, hiding in plain sight for seventy-five years inside one of the most studied viruses in science.
PreS sits inside the lambda phage, a virus that naturally hunts E. coli bacteria. Acting as a molecular switch, it hijacks the bacterium's own cellular machinery, forcing it to produce copies of the phage until the cell swells and ruptures. Where antibiotics have become blunt and increasingly ineffective instruments, this mechanism offers something different — biological precision at the molecular level.
The discovery was not the original goal. Dr. Sahar Melamed and his team, including PhD student Aviezer Silverman, MSc student Raneem Nashef, and computational biologist Reut Wasserman, were using a technique called RIL-seq — which chemically links interacting RNA molecules and sequences them — to map the molecular dialogue between phage and host during infection. PreS emerged from that eavesdropping: a layer of communication that had been invisible to science until now.
The timing carries weight. Phage therapy was pioneered in 1917 by Félix d'Hérelle, then largely shelved when penicillin arrived. Today, as bacteria evolve resistance to nearly every antibiotic, the field has returned with new urgency. In Israel, the Israel Phage Therapy Center — established in 2018 with Hadassah Medical Center — has treated soldiers wounded in Gaza who contracted resistant infections. Some did not survive.
What PreS unlocks is not just a mechanism, but a method of thinking. If scientists can chart how different phages manipulate different bacteria at the molecular level, they can begin to engineer therapies that are more targeted and harder to evade. Published in Molecular Cell, the research marks a turning point — the beginning of a real conversation between science and the viruses it may soon ask to fight on our behalf.
Antibiotic-resistant bacteria kill. In 2019 alone, they were directly responsible for 1.27 million deaths worldwide. In Israel, roughly 5,000 people die each year from infections caused by bacteria that no longer respond to the drugs designed to stop them. The problem is accelerating, and conventional medicine has few answers left. This is why a team of researchers at Hebrew University of Jerusalem spent months studying a molecule so small it had escaped notice for seventy-five years—even in one of the most scrutinized viruses in science.
The molecule is called PreS, and it is an RNA switch that sits inside the lambda phage, a virus that hunts E. coli bacteria. What PreS does is remarkable in its simplicity: it hijacks the bacterial cell's own machinery, forcing it to manufacture copies of the phage instead of performing its normal functions. As more and more phages are produced inside the cell, they accumulate until the pressure becomes too great. The cell ruptures. The bacterium dies. The phages spread to infect other bacteria in the population. It is a form of biological precision that antibiotics, blunt instruments by comparison, can no longer achieve against resistant strains.
Dr. Sahar Melamed, who leads the research group at Hebrew University, did not set out to find PreS. Instead, he and his team—PhD student Aviezer Silverman, MSc student Raneem Nashef, and computational biologist Reut Wasserman, working with Prof. Ido Golding's group at the University of Illinois Urbana-Champaign—were using a technique called RIL-seq to listen to RNA molecules communicate with each other inside infected bacterial cells. RIL-seq works by chemically "gluing" interacting RNA molecules together and then sequencing them to reveal which pairs are connected. Melamed had developed the method during his postdoctoral work and adapted it here to map interactions that occur specifically while a phage is taking over a bacterium. The discovery of PreS emerged from this eavesdropping on molecular conversation—a layer of communication between phage and host that had remained invisible to science until now.
The timing of this discovery is not incidental. Phage therapy, the use of bacteria-eating viruses to treat infections, was pioneered more than a century ago by French-Canadian microbiologist Félix d'Hérelle in 1917. He named it from the Greek word for "to devour." But when penicillin arrived, the field largely abandoned phage research. Why pursue viruses when antibiotics seemed to offer a cleaner, more controllable solution? Now, as bacteria have evolved resistance to nearly every antibiotic in the arsenal, researchers have returned to phages with new urgency. In Israel, the Israel Phage Therapy Center was established in 2018 in partnership with Hadassah Medical Center. During the two-year war in Gaza, dozens of Israeli soldiers contracted infections from antibiotic-resistant bacteria. One soldier, Hanan Drori, died from a severe fungal infection. The center's researchers have begun naming newly discovered phages in memory of those killed.
What makes PreS significant is not just that it exists, but that understanding how it works opens a door to rational design of phage therapies. If scientists can identify the molecular mechanisms by which phages manipulate bacterial cells, they can potentially engineer phages to be more effective, more targeted, and harder for bacteria to resist. Melamed's next step is to search for similar RNA molecules in other phages, to build a map of how different viruses hijack different bacterial systems. The research, published in the journal Molecular Cell on Thursday, represents a shift in how scientists think about the conversation between phage and host—a conversation that, for the first time, they are beginning to understand at the molecular level. As antibiotic resistance continues to spread, this understanding may prove to be the difference between a therapy that works and one that fails.
Citas Notables
Antibiotic resistance is one of the most serious global health threats of our time, and understanding how phages operate can aid scientists in furthering research and therapies that might help fight antibiotic-resistant bacteria.— Dr. Sahar Melamed, Hebrew University of Jerusalem
PreS hijacks the bacterium's replication machinery and enables the phage to reproduce efficiently inside individual bacteria while maximizing its spread through the bacterial population.— Dr. Sahar Melamed
La Conversación del Hearth Otra perspectiva de la historia
Why does it matter that PreS was hiding in a virus that's been studied for seventy-five years?
Because it shows us that we've been looking at phages without really understanding how they work at the molecular level. We knew the outcome—the phage kills the bacterium—but not the mechanism. PreS is that mechanism. Once you know the mechanism, you can design better treatments.
How does a phage actually kill a bacterium?
It hijacks the cell's own machinery. PreS forces the bacterium to make copies of the phage instead of doing what it normally does. Eventually there are so many phages inside that the cell bursts open. The bacterium is destroyed, and the phages spread to other bacteria.
That sounds elegant, but why can't bacteria develop resistance to phages the way they've resisted antibiotics?
They can, and they do. But phages evolve faster than bacteria. It's an arms race, but the phages have the advantage of speed. That's part of why phage therapy is so promising—it's not a static drug that bacteria can simply learn to ignore.
You mentioned that researchers in Israel have started naming phages after people who died. That's a striking detail.
It is. The war brought the problem into sharp focus. Soldiers were getting infections that antibiotics couldn't touch. Some died. The researchers at the Phage Therapy Center are not just doing abstract science—they're working on something that could have saved those lives. The naming is a way of acknowledging that.
What happens next with this discovery?
Melamed's team is now looking for similar RNA molecules in other phages. If they can map how different phages manipulate different bacterial systems, they can start designing phages that are more effective against specific resistant bacteria. That's the real prize—moving from understanding how phages work to engineering them to work better.