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NEW YORK, Mar 20, 2001 (United Press International via COMTEX) -- A new approach for killing streptococci bacteria may offer promise for combating many bacteria, including those which have developed antibiotic resistance. The treatment involves the use of enzymes created by bacteriophages -- tiny viruses that infect bacteria, replicate in them, and then use enzymes to cut through the bacterial cell walls and escape. The most important benefit of the new strategy may lie in preventing transmission of bacterial diseases rather than in curing them.
Researchers at Rockefeller University in New York had for years used an enzyme as a probe or tool in the study of streptococcal bacteria. Now they have discovered that the same enzyme may be used to destroy various strains of streptococci, which can cause everything from strep throat to pneumonia and flesh-eating diseases. While unlikely to cure an established infection, the enzyme wipes out the source of the disease bacteria on mucosal surfaces, reducing the chance it will cause infection in the first place, or that it will be as easily transmitted.
Dr. Vincent Fischetti and his colleagues report their findings in the March 20 issue of Proceedings of the National Academy of Sciences. The research involves an elegant but simple experiment. "In fact, the work is so simple that the first question I am usually asked is, 'Why didn't anybody else think of this before?," said Fischetti..
His lab works with bacteriophages, viruses that infect bacterial cells, replicate within them, and create enzymes that cut through the bacterial cell wall in order to move on and infect neighboring cells. Because these so-called lytic enzymes specifically kill the species in which they are produced, Fischetti wondered if they could be used to eliminate pathogenic bacteria without disturbing other normal microflora. This possibility would avoid one traditional problem with antibiotics, which wipe out both pathogenic and "good" microorganisms.
He and his team took a bacteriophage cloned out the phage enzyme, known as the streptococcal bacteriophage C1, which is specific for groups A, C and E streptococci. First they added a tiny portion -- ten nannograms -- of the enzyme to ten million organisms in a test tube. "In five seconds the organisms were all killed. The enzyme just knocks holes in the cell wall. The bacteria explode. I was flabbergasted," says Fischetti.
The researchers next conducted a basic animal study. They introduced a dose of the phage enzyme into the oral cavity of mice, followed by a dose of live group A streptococci. The enzyme protected against colonization -- only. 28.5 percent of the mice given the enzyme became infected versus 70 percent of the untreated animals. The study suggested the potential for eliminating the bacteria from the upper respiratory mucosal tract, reducing the incidence or transmission of related diseases. Because no safety problems surfaced in the animal studies, Fischetti and his colleagues are looking forward to Phase One trials in humans.
"Of course no one has a crystal ball, and we will have to wait and see what happens when you try this approach in humans, but it is very exciting work," says Dr. Joseph Ferretti, a research professor of microbiology and immunology at the University of Oklahoma Health Sciences Center in Oklahoma City and a specialist in the study of streptococci. Ferretti points out that the strategy may prove effective against streptococcal pneumonia, which has a high incidence of antibiotic resistance.
Phage enzymes developed for other strains of streptococci may one day be equally important. Group B streptococcal infection affects as many as 40 percent of pregnant women. The infection, if transmitted to the baby during birth, can cause septicemia or neonatal meningitis, which can be fatal.
"Right now many women must be given antibiotics in the third trimester, whereas eventually we might simply be able to use a spray or a tampon soaked with the phage enzyme and prevent transmission," says Fischetti.
He also envisions the possible use -- in daycare centers or nursing homes -- of aerosol sprays, perhaps twice a week, to prevent transmission of strep throat or pneumonia.
If the treatment strategy is successful in humans, it will certainly be attempted with bacteria other than streptococci. Right now the research suggests that the phage enzyme can wipe out certain streptococci on contact on mucosal surfaces. Fischetti is beginning studies to see if the enzyme can survive in blood. He doubts that the enzyme can attack bacteria that survive intracellularly, but no one knows.
"The approach has restricted use and delivering the enzyme to the proper surfaces may be difficult," says Dr. William Jacobs, professor of microbiology and immunology at Albert Einstein College of Medicine. "For instance, with tuberculosis, getting it to all the tissue in the lungs might be difficult. For now, the approach seems to work great on strep, and that is wonderful."
Fischetti says that while the enzyme might not cure TB, it might help prevent the transmission of any bacteria, including tuberculosis, that can be transmitted by saliva.
Whether the use of enzymes might trigger an antibody response in humans, or whether there may be some element in serum that degrades the enzyme remains to be seen.
"If it works, it works," says Dr. John Robbins, Chief of the Laboratory for Developmental and Molecular Immunity at the National Institutes of Health. "Everything they are saying, I am for. but we will just have to see. Antibodies to enzymes generally form very quickly. Still, this is an approach that is different and there is no reason not to give it a fair trial."
Fischetti's group has recently received a grant from the Defense Department, partly because of the military's concern over controlling strep infection among recruits. Recruits currently receive penicillin prophylactically, but antibiotic resistance has prompted a search for alternative approaches.
However, preventing strep throat, Fischetti believes, is not the only reason for the military's interest. "They see the possibility that phage enzymes could be used as a way of countering organisms used in biowarfare, like anthrax or plague," he said.
So, too, have Russian investigators, with whom Fischetti's team is beginning to cooperate. Russians have studied bacteriophages for years, although -- as Fischetti hastens to point out -- they never thought of using the phage enzymes to wipe out bacteria. "We are now able to help each other," he says. "They have many bacteriophages, and we are able to identify the gene for the specific enzyme."
(Reported by Katie Leishman in Los Angeles, Calif.)
Copyright 2001 by United Press International.
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