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Mar 01, 2014 Discover Magazine March, 2014 Infections 7447001372 3 Infections Infected In the face of antibiotic resistance, phage therapy may be coming to a pharmacy near you. BY LINDA MARSA ~ It was a guerrilla assault worthy -,of the takedown of Osama bin Laden. But in this case, the assassins A phage is a type of virus that attacks and infiltrates bacteria. In this digital rendering, were intrepid viral invaders. In Andrew T-bacteriophages are on the attack, injecting their genetic material into the bacteria. Camilli's molecular biology lab at Tufts University in Boston, researchers found Alexander Sulakvelidze, a phage expert tions worked, and sometimes they didn't. the telltale footprints of a startling at the Emerging Pathogens Institute at Also, people occasionally became sick attack against cholera, a deadly bacterial the University of Florida in Gainesville. after ingesting the tiny microbes because disease. They were analyzing the DNA Without a way to manage infections, the treatments weren't purified properly. sequences of tiny viruses called bacte­ surgeries ranging from simple procedures Western physicians discarded them once riophages (literally, "bacteria eaters") to complex organ transplants would the more reliable antibiotics became lurking in the stool samples of cholera become risky, he explains: "You have a widely available after World War II. patients. The phages' DNA contained very real and alarming possibility that However, Soviet scientists figured some of the genes from another patients will either die or will develop out how to make phages more effec­ bacteria's inunune system. Somehow, the complications. " Many researchers believe tive - advances in molecular biology tiny phages sneaked in and overpowered it's time to look beyond antibiotics. techniques allowed biologists to identify the much larger cholera cells, using a big better matches between phages and their chunk of this stolen immune system. HUMBLE ORIGINS intended prey - although their less rig­ "We were surprised because it's the Bacteriophages, about 100 times smaller orous studies in Russian journals were first known example of any virus that than bacteria, are the most abundant life ignored by cold warriors in the West. has captured and commandeered [an] forms on Earth, inhabiting water, plants, Phages are still routinely used in immune system," says Camilli. "The se~age and our digestive tract. They do Eastern Europe and, more recently, in phages clearly have gained the upper their dirty work by infiltrating bacteria, Asia. The muddy-looking serums are hand, and studying how they do it can including disease-causing germs, and often sold over the counter in glass vials eventually open the door for treating destroying them from within: After latch­ and dabbed on wounds or taken orally. A cholera with phages." ing onto bacteria, the phages bore inside handful of desperate Americans - strug­ Camilli's research is part of a scientific and hijack the bacteria's genetic machin­ gling with treatment-resistant infections, renaissance into phage therapy, virtually ery, turning them into phage factories diabetic ulcers or other chronic wounds unheard of in the West. Early in the 20th that eventually make so many copies that - have journeyed to a clinic in Tbilisi, century, doctors worldwide used these the cells burst, killing off the host. Georgia, for the "phage miracle cure." bacteria-eating viruses to fight dysentery But the phages can be finicky and "I have used phages - almost and other dangerous pathogens, only to unpredictable. Each strain of phage is everyone I know has used phages," says abandon them after more effective anti­ highly targeted and has evolved to home Sulakvelidze, who was a rising scientific biotics emerged. But today, researchers in on specific bacteria, which means a star in his native Georgia and became a are turning to phages because antibiotics precise match between prey and predator director of the then-republic's version are losing their punch. is necessary for any phage-based treat­ of the Centers for Disease Control and The comeback of antibiotic-resistant ment to be effective. At first, in the 1920s Prevention at age 27. He conducted infections "would dramatically alter the and '30s, doctors didn't know about this phage research until the collapse of the practice of medicine," says microbiologist specificity, so sometimes the prepara­ Soviet Union in 1991. Twenty years 20 DISCOVERMAGAZINE.COM ago, when he arrived in the U.S. as a Along with other scientists, he now sleight of hand. Researchers aren't postdoctoral fellow at the University of focuses on human cures. He's currently sure how these tiny viruses got a chunk Maryland, he was shocked to find that working with the U.S. Army's Research of DNA from a bacterium's immune this therapy was virtually unknown here. Office on a project to fight shigellosis, a system, but they're looking into how But the tremendous progress in phage form of dysentery that kills almost a mil­ the viruses transformed this adaptive research of the past 10 years and the lion people a year, mostly young children. immune system into a weapon against urgency to find alternatives to antibiot­ Preliminary studies show phages are the deadly pathogens. "We don't know ics have made physicians more willing to effective in fighting antibiotic-resistant how this happens, although we do have look into phages, he says. ear infections and chronic ulcers, and some clues," says Camilli. Unraveling the some researchers suspect they might underlying mechanism could help pave PUTTING PHAGES TO WORK work on acne outbreaks. Phages the way toward making phages a targeted In 1998, Sulakvelidze helped found even neutralized the deadly MRSA therapy for diseases like cholera. the biotech company Intralytix, which (methicillin-resistant Staphylococcus Still, numerous stumbling blocks has successfully devised a number of aureus) superbugs that are resistant to remain before phages could become food safety products, including a spray most antibiotics and have become a part of our infectious disease arsenal. that uses phages to eradicate Listeria, serious problem in hospitals, nursing To gain regulatory approval, a drug is Salmonella and E. coli in foods before homes and intensive care units. "The normally tested in costly large-scale they reach stores. "When we first food safety preparations, the possible trials encompassing a large number formed, people would simply laugh at acne treatment, these are all potential of people - with about half getting us, and told us there is no way this can icebreakers - incremental steps toward a placebo, or dummy pill- to prove be commercialized," says Sulakvelidze. acceptance of phage therapeutics," says the treatment actually works. But since "It took a long time - more than four Graham Hatfull, a biology professor phages need to be targeted to specific years to get our first product approved and co-director of the University of bacteria to be effective, mixing and - but it did happen." Pittsburgh Bacteriophage Institute. matching phage preparations to fight On other fronts, Camilli's lab is busily infectious disease outbreaks isn't opti­ figuring out how the cholera-fighting mal for the one-size-fits-all approach phages - called ICPI - did their genetic that regulatory agencies like the FDA require for marketing approval. In contrast, antibiotics kill off a broad Phages and Food Safety spectrum of bacteria, making them easy The widespread use of phages to kill foodborne pathogens may to test in standard clinical trials. help·overcome regulatory reluctance to phage therapy. Out of Phages would require a less tradi­ nearly 48 million cases of foodborne illnesses every year, 128,000 tional approach to get official approval, result in hospitalizations and more than 3,000 result in deaths in such as the annual process for influenza the U.S. alone, according to the Centers for Disease Control and Prevention. In 2006, Intralytix secured FDA approval for vaccines in which manufacturers secure ListShield, a cocktail of six phages that is sprayed onto ready-to­ approval of new formulas based on the eat meat and poultry (like you'd find at the deli flu bug that is going around that year, counter) to control Listeria, which can cause a serious instead of conducting big clinical trials infection (Listeriosis) that has a 20 percent fatality rate. every time. Big Pharma is also leery In 2011 the company received clearance for EcoShield, a spray for red meat to combat Escherichia of investing millions in the capricious coli 0157:H7 (the culprit behind nearly 62,000 food­ microbes. The key question, Hatfull says, borne illnesses every year) and in 2013, for SalmoFresh, is when do we hit the turning point? which targets foods at high risk for Salmonella, such as "How bad does antibiotic resistance red meat and pOUltry. In a 2009 study, researchers from have to become that it initiates a the U.s. Department of Agriculture used EcoShield on fresh-cut lettuce and cantaloupe and found it reduces full-blown global initiative and we relax levels of E. coli to 100 times less within a day. regulatory procedures? We haven't quite "As a food safety tool, phages have great potential gotten there yet - but when we do, to reduce bacterial contamination," says study phages will be waiting in the wings." Ii] co-author Manan Sharma, a microbiologist with the USDA in Beltsville, Md. "Because phages are so present A tiny phage attacks in the environment, it doesn't seem to be a stretch to Linda Marsa is a Discover contributing an E. coli cell in these take something that is already present in food and reapply them editor and author of Fevered: How a Hotter false-color images in a more targeted way and get the food safety benefit." - LM Planet Will Harm Our Health and How We from a transmission electron microscope. Can Save Ourselves.
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