Bacteria-killing enzyme cures mice with fatal pneumonia

Mar 1 2009

Before the advent of antibiotics, pneumonia claimed so many lives - and was so feared - that it was called the "captain of the ship of death."

Now, at a time when the new antibiotics have proved futile against resistant strains of bacteria, researchers at Rockefeller University are using a different tactic to keep this ship at bay. Instead of using synthetic weapons, they are using nature's: an enzyme that has proved so effective at killing Streptococcus pneumoniae that it has been put on the front lines in the battle against infectious disease.

"The past decade has seen S. pneumoniae evolve new resistance mechanisms much more quickly than scientists have been able to develop antibiotics to combat them," says Vincent A. Fischetti, head of the Laboratory of Bacterial Pathogenesis and Immunology. "This enzyme represents one of the most promising therapeutic options to stop this arms race between S. pneumoniae and humans with a final blow."

According to some estimates, 5 to 10 percent of healthy adults and 15 to 40 percent of healthy children are carriers of S. pneumoniae, which normally resides in the nose. If the immune system doesn't keep these bacteria in check or an upper respiratory infection occurs, they can start to multiply and travel to different organs such as the lungs (causing pneumonia), brain (meningitis) or ears (otitis media), with sometimes fatal consequences. The prognosis is particularly bad in children and the elderly: In 2004 alone, 40 percent of children and older adults who developed pneumonia due to S. pneumoniae died of the disease.

The new research, which appears in the February issue of Critical Care Medicine, reveals that the enzyme Cpl-1, which is produced by bacteria-infecting viruses called bacteriophages, can successfully reach lung tissue in mice and reverse the symptoms of severe pneumococcal pneumonia. "Administering drugs through the blood is an effective way of treating disease, but not all drugs can remain active in that environment," says Fischetti. His team not only shows that Cpl-1 can make the trek but that it is also highly effective when it reaches its destination.

In their work, Fischetti and his German colleagues gave mice with pneumococcal pneumonia a dose of Cpl-1 or the antibiotic amoxicillin for comparison either 24 or 48 hours after establishment of pneumonia, and every 12 hours thereafter. Given at 24 hours, Cpl-1 eliminated the infection in 100 percent of the mice, compared to 85 percent with the antibiotic. Given at 48 hours, Cpl-1 cured fewer mice than amoxicillin, 40 percent versus 70 percent. Furthermore, in mice treated with multiple doses of Cp1-1 starting at 24 hours, the scientists observed that damage to the mice's lung tissue was completely reversed within 12 hours. When treatment began after 48 hours, the mice that survived showed no signs of tissue damage or difficulty in breathing. The results were similar in surviving animals treated with amoxicillin.

This isn't the first time that the Fischetti lab has shown that Cpl-1 targets and exclusively kills S. pneumoniae in mice. In earlier work, Fischetti and his colleagues showed that when the enzyme reaches the brain of mice that develop drug-resistant meningitis, it completely reverses the symptoms of disease. The lab has also shown that when Cpl-1 travels through the blood, it completely clears up S. pneumoniae secondary ear infections triggered by influenza.

"This technology is an attractive alternative to traditional antibiotics," says Fischetti. "And the more animal experiments we perform, we are finding that these enzymes can travel throughout the body to clear up potentially fatal infections."