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Phage Enzyme Can Kill Even Drug-Resistant Bacteria

Scientists have turned to nature once again for help in fighting deadly infections. Reporting in today's issue of Science, Rockefeller University researchers show that a natural enzyme derived from tiny viruses that live inside bacteria can successfully target and kill disease bacteria, including those that are resistant to drugs.

This novel approach may be used to prevent infections and, when used in combination with antibiotics, may provide a more efficient strategy for attacking bacterial invaders.

"A nasal spray containing this enzyme would prevent infections before they start," says Vincent A. Fischetti, Ph.D., principal investigator of the paper and co-head of the Laboratory of Bacterial Pathogenesis at Rockefeller University. "We would no longer have to wait for an infection to arise in order to treat it."

"Resistance to antibiotics is rapidly becoming a serious public health concern. These enzymes offer an alternative method for combating resistant pathogens," he adds.

Traditional antibiotics primarily attack bacteria that reside inside cells, while the recently discovered "bacteriophage" enzymes only kill disease bacteria that lie on the surface of cells.

In this study, Fischetti and his colleagues used these enzymes to eliminate Streptococcus pneumoniae present in the nasopharynx, an area between the back of the nose and throat, of mice. In addition, the researchers demonstrated that these enzymes can kill penicillin-resistant strains of this bacterium in a test tube.

S. pneumoniae normally lives on mucous membranes in the nose and throat of humans. It is from here that they strike out and cause infections, including ear infections, pneumonia and bacterial meningitis.

According to the Centers for Disease Control and Prevention (CDC), this pathogen is among the leading causes worldwide of illness and death in young children, persons with underlying medical conditions and the elderly. It is a special concern in nursing homes and day-care centers, where drug-resistant strains thrive.

Until now, there has been no strategy to remove the reservoir of S. pneumoniae from the noses and throats of humans. Yet, this "home base" provides an excellent target for controlling infections.

"This enzyme will kill pneumococci on mucous membranes within seconds," says Jutta Loeffler, M.D., first author of the paper and a postdoctoral fellow at Rockefeller. "By treating individuals carrying this bacterium with the enzyme, you could significantly reduce the reservoir of these bugs in the population and consequently reduce infection rates."

Such a decline in the number of worldwide infections would lessen the need for traditional antibiotics and subsequently ease the mounting drug-resistance problem.

Bacteriophage, or phage, can be found just about anywhere: in sewage and soil and any other locations where bacteria are found. As part of their normal lifecycle, these tiny viruses infect, replicate, then burst out of bacteria before infecting their next host.

Special phage enzymes, which punch holes in the bacterial cell wall, ensure the phage a rapid exit; without this outer layer of protection the bacteria essentially cannot hold themselves together, and, they explode.

Fischetti discovered that the phage enzymes also work when applied to the outside of the bacterial cells: by adding a few drops of phage enzyme to a test tube of millions of bacteria, he found that he could kill nearly all of them within a few seconds.

Because phage enzymes are specific for the species or strain of bacterium from which they were produced, cultivating a tailor-made killer for any bacterium of interest may be possible.

Last February, for example, Fischetti and colleagues reported the isolation of a phage enzyme specific for Group A streptococci, an infectious pathogen that causes strep throat and flesh-eating disease.

Human clinical trials testing the ability of a throat spray containing this enzyme to prevent strep throat are in the planning stages. (See news release at this URL.)

Another benefit of this approach, says Fischetti, is that it should not easily lead to enzyme resistance in the targeted organisms, as antibiotics tend to do.

Phage and bacteria evolved together over millions of years, and, as a result of this ongoing battle, the phage have ensured that their host bacterium will not find ways to thwart or resist their lifecycle; the enzymes they employ to get out of the bacteria target essential components of the bacterial cell wall that will be difficult to change.

To verify this theory that resistance will be a rare event, the researchers repeatedly exposed bacteria to increasing concentrations of the enzymes. Not once did resistance organisms develop, the scientists report in Science.

Moreover, these enzymes are unlikely to produce side effects. Antibiotics kill indiscriminately many different bacteria in a person's system, leading to such common side effects as intestinal problems. Because the phage enzymes only target the disease organism, they do not harm useful bacteria.

"We have always accepted the bad side effects of antibiotics as a consequence of killing the virulent bacteria," says Fischetti. "The unique thing about these enzymes is that they are targeted killers and therefore should result in minimal side effects."

However, it is important to note that these enzymes, which seem to excel at preventing infections, are unlikely to cure full-blown infections. Antibiotics can get at the bacteria inside our body's cells, but the phage enzymes cannot: they are too big to enter cells.

On the other hand, these enzymes are better at killing infectious bacteria that lie on the surface of the cells, or mucous membranes, where antibiotics are less effective. Consequently, a combination of these two strategies might prove to be a powerful weapon against infectious bacteria and, additionally, may reduce the amount of traditional antibiotics a person is required to take.

Fischetti and colleagues say that hospitals, day-care centers and nursing homes would greatly benefit from a treatment based on their latest phage enzyme against S. pneumoniae. These environments tend to foster infections, and because large amounts of antibiotics are used, the number of people infected with resistant strains of S. pneumoniae continues to rise. A pneumococcal vaccine is available for children and adults, but this technique is not perfect.

"Even with vaccination, children can still be colonized by other pneumococcal strains," says Loeffler. "But if you use this enzyme in addition to the vaccine, doctors might be able to reduce the reservoir of pneumococci in the population."

The idea of using bacteria's number one natural enemy to treat infections has been around for decades, but past attempts involved using the whole phage. It wasn't until Fischetti thought of using solely the enzymes of these tiny viruses that promising results arose.

"People probably didn't think of this strategy, perhaps because these enzymes help the phage get out of the bacteria, they work from the inside," says Fischetti. "It seems like such a simple idea now, to use these enzymes from the outside to kill bacteria."

Clinical trials with the new phage enzyme are currently in the planning stages.

The work is funded by the Defense Advanced Research Project Agency of the Department of Defense. Loeffler was sponsored by fellowships from the Swiss National Science Foundation and the Frieda Locher-Hofmann Foundation. - By Joseph Bonner

(Editor's Note: There are some interesting visual demonstrations of these enzymes wiping out millions of bacteria in Quicktime movie format at this URL and at this one.)

[Contact: Joseph Bonner]






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