Virus Battles Drug-Resistant Infections

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This story originally appeared in the winter 2025 issue of UC San Diego Magazine as “Anti-Hero.”

It’s an evolutionary battle, an endless competition for survival, that has spanned millions of years. Within this epic tale for the ages, the skillful characters are mighty, but very, very tiny — they’re microscopic. It’s bacteria versus viruses. (And in this story, viruses are actually the good guys.)

While the COVID-19 pandemic brought fear and concern about the spread of all viral infections, UC San Diego scientists are viewing some viruses in a new light as potential allies for the rising scourge of bacterial infections. “Bacteriophages,” which literally translates from Greek to “bacteria eaters,” are the most abundant organisms on the planet. These viruses, or “phages,” thrive comfortably in soil, water, food products and even inside our bodies. And now, based on new UC San Diego discoveries, they may prove to be a solution for drug-resistant bacterial infections.

Battle Royale

Throughout time, viruses and bacteria have engaged in an endless competition for survival. Bacteria are ever-evolving to counteract the attack of the viruses seeking to infect them. This “evolutionary arms race” has pushed viruses to create new adaptations around bacteria’s freshly updated defenses.

The use of phages as a treatment for bacterial infections has a long tradition. In the years leading up to World War II, scientists were evaluating various phage species for medicinal purposes. But once penicillin became commercially available in 1945, the so-called “Golden Age of Antibiotics” stalled any potential phage therapy developments. 

Today, traditional antibiotic treatments have become increasingly ineffective due to the quick evolution and adaptation of the bacteria these medicines fight. Additionally, drug-resistant bacterial infections have caused roughly 1 million deaths each year from 1990 to 2021 and are predicted to spike in the coming years, leading to nearly 40 million deaths by 2050. Researchers are once again turning to phage therapy as a promising treatment. 

Stealth Mode

While previous research concentrated on small phages as potential healing agents, scientists are now focusing on phages that are considerably larger. Details of these “jumbo phages” — which are actually 1/500th the diameter of a human hair but larger than the human-infecting coronavirus — were largely a mystery until recently.

Cutting-edge imaging technologies such as cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) allow UC San Diego researchers to delve into the biological functions of jumbo phages and unravel their key features. These technologies employ a method of flash-cooling samples to freeze molecules in place and provide new insights on previously unseen processes.

In 2022, research led by Joe Pogliano and Elizabeth Villa, professors in the School of Biological Sciences, and  Kevin Corbett, professor in the School of Medicine, found that jumbo phages feature a shielded compartment that functions similarly to the nucleus of human cells. The compartment is formed from a protein and protects the virus’s key genetic material, which is needed to replicate and spread within bacteria as part of the infection takeover process. This finding is “unlike anything seen elsewhere in nature,” says Villa. (The researchers named the protein “chimallin” after the ancient shields used by Aztec warriors, which led to the entire family of phages being named chimalliviruses.)

More recently, researchers and colleagues at UC Berkeley discovered that chimalliviruses also create a stealth structure within bacteria that serves as a type of cloaking mechanism to hide valuable phage DNA material to avoid triggering bacteria’s immune systems.

“Chimalliviruses and their ‘weird biology’ open a completely new era that we think will blow open our ability to create new therapy tools,” says Villa, leader of a $10 million initiative at Howard Hughes Medical Institute focused on unlocking the therapeutic potential of jumbo phages. The project brings together UC San Diego researchers with scientists at the J. Craig Venter Institute and Yale University. 

The Right Phage

Finding the optimal jumbo phages for future treatments against antibiotic resistance is key to combating various strains of bacteria, including Pseudomonas, a bacterium that plagues patients in hospitals and other health settings, as well as staph (Staphylococcus) and E. coli (Escherichia) infections. The researchers hope to bioengineer phages with genetic payloads that can deliver therapeutics to those suffering from bacterial infections. 

“You can’t just pick any phage off the shelf and throw it on any bacteria as we did with penicillin,” says Pogliano. “Our goal is to create designer phages that have a broad host range so they can infect a large number of bacterial strains.”

The recent discoveries of phage biological functions work in synchronicity with UC San Diego’s Center for Innovative Phage Applications and Therapeutics, the first dedicated phage therapy center in the U.S., focusing on clinical applications in treating challenging bacterial infections.

And so, the battle continues — but this time, viruses may be the key to our salvation and victory.