Scientists in Australia have figured out how to cripple an antibiotic-resistant superbug that's responsible for up to one in five bacterial infections in intensive care units by using bacteriophage viruses.
Their study, published in Nature Microbiology last week, paints a clearer picture of the bacteria’s evolution by uncovering previously elusive trade-offs in Acinetobacter baumannii between resistance to phages and resistance to antibiotics, and suggests those trade-offs could be exploited in clinical treatments.
“That’s the model that we are proposing: That one-two punch,” Fernando Gordillo Altamirano, lead author of the study and a Ph.D. student at Monash University’s School of Biological Sciences in Australia, said in an interview with The Academic Times.
“You hit it with phages,” he continued. “When the bacteria become resistant to the phage, it becomes resensitized to the antibiotic. So boom, you hit it with the antibiotic, and hopefully the patient makes it out all right.”
A. baumannii can plague hospital patients by attaching to medical devices like ventilator tubes and catheters to infect wounds and the lungs, urinary tract and bloodstream. Research and development of new antibiotics for the carbapenem-resistant superbug is a critical priority of the World Health Organization.
Enter bacteriophages, or “bacteria eaters.” These viruses typically infect a single type of bacteria and are not harmful to humans. In fact, phages are the body’s most plentiful microbe, and besides controlling and manipulating bacterial populations, they also prevent infection and disease.
Once a popular concept, phage therapy for infections was largely abandoned around seven decades ago, when antibiotics came into the picture. It is now experiencing “a well-deserved rebirth,” however, due to more widespread antibiotic resistance, Gordillo Altamirano and his Ph.D. supervisor Jeremy Barr wrote in a 2019 literature review.
As senior author of the latest study, Barr brought unique insights from his involvement in a high-profile case in which a patient suffering from a life-threatening A. baumannii infection received successful phage therapy in the U.S. Doctors responded to strain mutations by remixing their phage cocktails and ultimately resensitizing the superbug to one antibiotic, but exactly how this happened was unclear.
That was the starting point for the latest research. Studies on other species have found trade-offs between phage resistance and bacterial fitness: When a bacteria evolves to resist a phage, it can lose flagella or another structure, for example. But no such trade-off had yet been documented for A. baumannii.
So the researchers drew from wastewater samples from around Australia to isolate eight phages, ultimately focusing on ΦFG02 and ΦCO01. When they were mixed with A. baumannii in the lab, phage-resistant mutants emerged.
After searching the mutants for several of the usual trade-off implications such as speed of growth, Gordillo Altamirano just said, “Screw it,” and decided to look at the bacteria’s capsule production under the microscope, an easy five-minute task.
That’s how the team realized the phage-resistant superbug lacked its usual capsule, or outer layer, to which the phages would normally attach through a receptor on the bacteria’s viscous surface, as established by the study. But when confronted with phages, the researchers found, A. baumannii genes that would normally produce the capsule mutated, and the capsule was dropped.
“That was the eureka moment, when I decided to test for the capsule,” Gordillo Altamirano said.
It also created an opening for researchers to go in and test nine antibiotics on the phage-resistant superbug. And they found it was now susceptible to three of the antibiotics, and could be killed with a lower dosage.
The findings from the primarily laboratory-based research are mostly in vitro, with some animal work documenting activity in mice. But in a follow-up paper, Gordillo Altamirano is conducting pre-clinical trials with new animal models in hopes of demonstrating how phages and antibiotics can work better together than either one can alone, or no treatment at all.
“Without giving too much away, it’s looking great,” he said.
Other early stage clinical trials are advancing phage therapy. Gordillo Altamirano noted a European trial treating patients with burn wound infections, and an Australian study where more than a dozen hospital patients were safely treated for infections from the superbug Staphylococcus aureus.
“With further research, with further efforts, with further education to the public and the lawmakers,” he said, “We are hopeful that we can bring phage therapy to a wider audience.”
But there are limited options for accessing phage therapy, he explained. Patients can participate in those clinical trials; pursue medical tourism in places like Georgia, Russia and Poland; or obtain regulatory authorization for compassionate use in Australia, parts of Europe or the U.S., as was the case with the patient in Barr’s previous study.
At the Yale School of Medicine's clinical practice, research scientists and doctors have used the experimental treatment to benefit patients who are especially vulnerable to infection, such as those with cystic fibrosis. Yale notes that antibiotic-resistant bacteria cause one death every 15 minutes in the U.S., according to the Centers for Disease Control and Prevention.
The study “Bacteriophage-resistant Acinetobacter baumannii are resensitized to antimicrobials,” published Jan. 11 in Nature Microbiology, was authored by Fernando Gordillo Altamirano, John H. Forsyth, Ruzeen Patwa, Xenia Kostoulias, Michael Trim, Dinesh Subedi, Stuart K. Archer, Faye C. Morris, Cody Oliveira, Luisa Kielty, Denis Korneev, Moira K. O’Bryan, Trevor J. Lithgow, Anton Y. Peleg and Jeremy J. Barr, Monash University.