The global rise in antibiotic resistance is making bacterial infections harder to treat and increasing the risk of disease spread, severe illness, and death. Once considered miracle drugs, antibiotics are now losing their effectiveness against ever-evolving bacteria. One company is aiming to treat infections with a different strategy: arming tiny viruses called bacteriophages with Crispr.
Known as phages for short, these viruses naturally infect and kill bacteria. Locus Biosciences of North Carolina is adding the gene-editing tool Crispr to the phages’ armory to boost their killing ability. The company is testing the approach against urinary tract infections, or UTIs, caused by E. coli bacteria. Results from a small trial published in August suggest the experimental treatment has promise, but larger studies will be needed to confirm its benefits.
Phages exist everywhere that bacteria do, including sewers and soil, and there are thousands of different types. Whereas antibiotics kill bacteria indiscriminately—including the beneficial kind—phages have evolved to be selective in the strains or species of bacteria they target. This makes them an attractive alternative for treating infections.
In fact, phages were discovered more than 100 years ago and were used as medical treatments for a range of different infections in the early 20th century. But with the advent of antibiotics, phages fell out of use, except in the former Soviet Union, where antibiotics were not as accessible. Phage preparations were difficult to prepare, and scientists were skeptical about how well they worked.
Bacteriophages under magnification.
Photograph: Locus Biosciences
Researchers are once again interested in phage therapy as the threat of antibiotic resistance grows. Often used in cases of chronic or life-threatening infections when antibiotics fail, scientists comb through collections of phages searching for ones that best match the problematic bacteria living inside a patient.
Locus’s therapy is actually a cocktail of six phages. The company used artificial intelligence to predict a combination that would be effective against E. coli. Three of the phages are “lytic,” meaning work by infecting E. coli cells and causing them to burst open. The other three are engineered to contain Crispr to enhance their effectiveness. Once inside their target cells, these phages use the Crispr system to home in on a crucial site in the E. coli genome and start degrading the bacteria’s DNA.
Some phages are really good at getting into bacterial cells but not good at killing them. “That’s where gene editing comes in,” explains Paul Garofolo, CEO of Locus. He says the therapy is meant to “reach into the human body and remove a targeted bacterial species without touching anything else.”
In a Phase 2 trial, 16 women received a three-day course of the phage cocktail, along with Bactrim, a commonly prescribed antibiotic for UTIs. Within four hours of the first treatment, levels of E. coli in the urine rapidly declined, and were maintained through the end of the 10-day study period. By that time, UTI symptoms in all of the participants had cleared up, and levels of E. coli were low enough in 14 out of 16 women that they were considered cured.
The findings were reported August 9 in the journal The Lancet Infectious Diseases. The Biomedical Advanced Research and Development Authority, or BARDA, part of the US Department of Health and Human Services, is co-developing the therapy.
UTIs are incredibly common, and roughly half of women will have a UTI in their lifetime. More than 80 percent of infections are caused by E. coli, and in a 2022 report, the World Health Organization found that one in five UTI infections caused by E. coli showed reduced susceptibility to standard antibiotics like ampicillin, co-trimoxazole, and fluoroquinolones.
While phage therapy is common in the Republic of Georgia and Poland, it is not licensed in the US. However, it is used experimentally in certain cases with permission from the US Food and Drug Administration. A major challenge with commercializing phage therapy is that it’s often personalized to individual patients and thus difficult to scale. Finding the right phage for treatment can take time, and then batches of phages need to be grown and purified. But using a fixed cocktail like Locus’s would mean the therapy could be more easily scaled.
And there’s another potential benefit. “The Crispr-enhanced phages allow for degradation of the bacterial genome and would bypass several mechanisms by which bacteria can become resistant to phage,” says Saima Aslam, a professor of medicine at the University of California, San Diego, who studies phages but is not involved in the development of the Locus therapy. “Theoretically, this may prevent regrowth of phage-resistant bacteria and thus lead to more effective treatment.”
Photograph: Locus Biosciences
Phillippe Zimmern, a professor of urology at UT Southwestern Medical Center, says it’s an interesting approach, but administering the therapy is not exactly convenient for patients. In the trial, the phage cocktail was given via a catheter that’s inserted into the bladder through the urethra, which would likely be uncomfortable for patients with UTIs. Participants also had to come to an outpatient clinic to receive the treatment three days in a row. “Yes, antibiotic resistance is a big problem,” Zimmern says. “But they have to give some thought as to how doable this is and how accepted it will be by patients.”
Garofolo says the company intends to work on more user-friendly formulations and dosing, which could include a pill or drinkable liquid. But he notes that the phage therapy is intended for patients with recurrent UTIs, not a first-time infection.
The current study also did not have a control arm, so Zimmern says it’s hard to know how much of the treatment’s efficacy is due to the phage cocktail or the antibiotic, Bactrim. In their paper, the authors say 11 of the 14 patients’ E. coli was resistant to Bactrim at the start of the study, showing that the engineered phage cocktail had an added benefit. There’s evidence that antibiotics may work synergistically with phages, so Garofolo says the two together could be more beneficial than the phage therapy on its own.
Locus is now beginning the second part of the trial, which will include a control group that will receive just the Bactrim and an experimental group that will get Bactrim plus the phage cocktail. That study will include up to 288 participants.
