This year the world awakened to the fact that the most powerful and sophisticated species on earth is tragically vulnerable to the tiniest and most basic of creatures. Infectious disease specialists have been warning about this for decades. And the threat comes not only from novel viruses, such as the one causing COVID-19, that jump from animals to humans but also from microbial monsters that we have helped to create through our cavalier use of antibiotics: treatment-resistant bacteria such as MRSA (methicillin-resistant Staphylococcus aureus) and multidrug-resistant Acinetobacter baumannii, sometimes dubbed “Iraqibacter” because so many soldiers returning from Iraq were infected with it. The World Health Organization has predicted that deaths from resistant “superbugs” will rise from roughly 700,000 a year today to nearly 10 million by 2050.
But in a splendid irony, it may turn out that viruses, so often seen as nemeses, could be our saviors in fighting a host of killer infections. As the threat from drug-resistant bacteria has grown and the development of new antibiotics has stalled, researchers have turned their attention to bacteriophages—literally, bacteria eaters. Viruses in this class are believed to be the oldest and most numerous organisms on earth. And like guided missiles, each type has evolved to seek and destroy a specific type of bacteria. Phage therapy has long been used in eastern Europe to battle infections, but after modern antibiotics arrived in the 1940s, it was largely ignored. Interest began to pick up in this century “because the resistance issue was getting worse and worse,” says Vincent Fischetti, who heads the laboratory of bacterial pathogenesis and immunology at the Rockefeller University. With modern techniques, virologists can precisely match just the right phages to a specific strain of superbug—with sometimes astonishing results.
Tom Patterson, for example, was resurrected from an overwhelming Iraqibacter infection after his wife, Steffanie Strathdee, an infectious disease epidemiologist, scoured the world for phages that might save him. The couple, both professors at the University of California, San Diego, tell his story in their 2019 book The Perfect Predator. Strathdee has since co-founded U.C.S.D.'s Center for Innovative Phage Applications and Therapeutics.
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For now phage therapy remains experimental. In most cases, it involves making custom cocktails of several phages shown to be active in vitro against an individual patient's bug. In Patterson's case, nine different phages were used in various cocktails injected into his bloodstream multiple times a day over 18 weeks. Strathdee envisions creating a library “with tens of thousands of phages, already purified, characterized and sequenced,” for medical mixologists to draw on. Researchers are also developing premixed phage cocktails for some of the more common superbug strains.
The effort that is furthest along, however, relies on a phage enzyme called a lysin rather than on whole phages. After multiplying inside a bacterium, phages use lysins to break through the cell wall of their host, instantly killing it. A purified lysin made from a phage gene isolated in Fischetti's lab was tested in a phase 2 trial with 116 patients suffering from staph infections of the blood or heart, including 43 with MRSA strains. The results led the FDA to designate the lysin, known as exebacase, a “breakthrough therapy,” meaning it will be fast-tracked for approval if a phase 3 trial, now underway, bears out the findings.
The full phase 2 results have not been published, but “what really grabbed a lot of attention was what we saw in the subgroup with MRSA,” says Cara Cassino, chief medical officer at ContraFect, the biotech firm developing exebacase. The infection was cleared in 74 percent of MRSA patients given the lysin plus standard antibiotics but in only 31 percent of those who got antibiotics plus a placebo. The respective mortality rates after 30 days were 3.7 and 25 percent, Cassino says. Other lysin drugs are in the pipeline at ContraFect and elsewhere.
Lysins work synergistically with standard antibiotics, Fischetti says; they can pierce the walls of superbugs, enabling the drugs to do their job. Lysins also clear up biofilms—slimy layers of bacteria, carbohydrates and gunk—that cause lasting infections not readily cured by antibiotics. Another advantage is specificity: lysins kill their target without collateral damage to the microbiome.
Phage and lysin therapies still have a ways to go, but at a time when much of the world is besieged by a virus, it's good to know that these tiny invaders may someday save us.
