Mar. 20, 2001 Researchers at The Rockefeller University have discovered a powerful new way to destroy on contact the bacteria that cause strep throat, flesh-eating disease and a variety of other infections. The technique, which may not cause the bacteria to evolve resistant strains as antibiotics do, also could have applications for many other bacterial diseases. The findings are reported in the March 20 issue of Proceedings of the National Academy of Sciences (Early Edition Issue No. 12).
The new method uses enzymes produced by bacteriophages, tiny viruses that infect bacterial cells, make copies of themselves and then exit to infect other cells. The bacteriophages (or "phages") produce the enzymes after they have finished replication and need to dissolve the bacterial cell wall in order to escape. Rockefeller University Professor Vincent Fischetti, Ph.D., who led the research, employs these same enzymes to attack the bacteria, Group A streptococci, from the outside. The effect is remarkable.
"It kills the target bacteria instantly. It’s amazing—instantly," says Fischetti, co-head of the Laboratory of Bacterial Pathogenesis. "It does this by punching holes in the cell walls. We can take 10 million organisms in a test tube, add a very small bit of enzyme, and five seconds later, they are all dead. Nothing other than strong chemical agents can kill bacteria this quickly."
In addition to being incredibly potent, the phage enzymes also are highly specific. Fischetti says every type of bacteria has a corresponding phage that infects it. An enzyme made by a streptococcus phage will, when purified, kill only certain streptococci when applied to the microbes on mucous membranes, leaving harmless bacteria alone. "It’s what we call targeted killing, in which we kill only the disease bacteria without disturbing the normal bacteria needed for health, unlike antibiotics which kill everything," he says.
At present, the lab harvests the enzymes from phages that have infected bacteria, but they have the ability to make it artificially if necessary. Fischetti says that eventually production costs could be as low as 10 cents per dose.
Strep throat is one of many diseases caused by Group A streptococci. Although not life-threatening in itself, strep throat can develop into rheumatic fever, which permanently damages the heart. At any one time, up to one-fifth of the population carries group A strep in their throats, and each year 30 percent of children develop strep throat infections.
"The phage enzymes will not likely cure an infection—its importance lies in lowering the chance that strep will cause infection in the first place," Fischetti says. "The enzymes would be used to eliminate the source of the disease bacteria, which in most cases are the human mucous membranes. The organisms are generally spread from an infected or colonized individual through contaminated saliva. The enzyme could be given in the form of a spray, administered at frequent intervals—such as once or twice a day—to maximize effectiveness."
The United States military has become interested in Fischetti’s work because of a need to control strep infections among its recruits. At present, all new recruits receive a penicillin injection to prevent strep outbreaks that inevitably occur in a group of people sharing close quarters. Antibiotic resistance compelled the military to try shifting away from such routine use of the drug. The hope is that giving the phage enzyme to each recruit once or twice a day will allow control of strep without this hindrance. The same approach could be used with children in day-care centers and schools.
The technology could prove even more valuable in developing countries, where rheumatic fever is a major cause of heart disease in children. Controlling streptococci in the population would lessen the chance of someone being exposed to strep throat, which would reduce cases of rheumatic fever.
After phages were discovered in 1917, researchers initially thought they would provide an effective way to kill bacteria. They soon learned, however, that phages must bind to specific receptors on the surface of bacteria before injecting their DNA; as bacteria evolve, they change their receptors and shut out the phages. Scientists would constantly have to develop new phages in order for them to be effective. Because of this drawback, phage therapy waned as a technology in most countries.
In recent years, though, antibiotics such as penicillin have lost their power, and health officials are warning that excessive use of antibiotics are only making bacterial threats worse. To avoid this problem, scientists have begun looking for effective alternatives.
Fischetti characterizes his findings as a "platform technology" in which phage enzymes from a wide range of disease bacteria may be used control these organisms. The method has potential applications that go beyond strep throat, by controlling common ear infections, staph infections and flesh-eating disease.
"I’ve been working with this enzyme for most of my career," he says. "Even though it seems obvious, we’ve only realized recently that you can use this method to kill bacteria. Phages have been involved with bacteria for eons, and they’ve figured out how to kill these organisms efficiently. Now we are just harnessing that power."
On a completely different note, Fischetti is also studying how bacteria and phage work together to cause infections in humans. In a recent paper in the March issue of Infection and Immunity, Thomas B. Broudy, a graduate fellow in Fischetti’s lab, describes for the first time a synergistic relationship between bacteria and phage that may explain how bacteria initially infect humans. The work shows that human throat cells can trigger phage to break out of streptococcal bacteria, allowing the newly released phage to infect other nearby strep cells, sometimes found in the human throat. But the bacteria benefit too, the researchers theorize, because phage toxins are also released when the bacteria burst, and these agents cause human tissue to be more susceptible to infection.
Support for the initial research was provided by a grant from New Horizons Diagnostics, a company in Columbia, Md.
John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of whom are on campus. Rockefeller University scientists have received the award in two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in physiology or medicine. At present, 32 faculty are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D. Celebrating its centennial anniversary in 2001, Rockefeller — the nation’s first biomedical research center—continues to lead the field in both scientific inquiry and the development of tomorrow’s scientists.
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