Researchers at Rockefeller University have developed a new method for combatting bacterial infections using lytic enzymes derived from bacteriophages.
Bacteriophages normally use lytic enzymes to release themselves from cells by lysing cell membranes once they have made many multiple copies of themselves within the cell. Rockefeller scientists in New York City have harnessed the ability of certain bacteriophages to lyse the walls of specific pathogenic bacteria and applied this skill towards treating infection from the bacteria.
Because the enzymes are derived from viruses that infect and kill specific bacteria, they are like “smart bombs” that target and kill only the species of bacteria for which they are designed, without harming the beneficial microorganisms that live in the nasal passages, throat, or intravenously.
“These are highly evolved enzymes that work efficiently and rapidly to kill specific bacteria,” said Vince Fischetti, the head of a bacterial pathogenesis and immunology laboratory at Rockefeller University. “The best use of these enzymes is to decolonize humans from carrying pathogenic bacteria in certain settings, such as hospitals, nursing homes and day care centers.”
Fischetti presented data from his phage work last week at the American Society for Microbiology’s conference on new phage biology in Key Biscayne, Fla.
So far, Fischetti’s group has isolated virus-derived lytic enzymes against Group A Streptococci, Group B Streptococci, Streptococcus pneumoniae, Staphylococcus aureus enterococci and anthrax (Bacillus anthracis).
Fischetti said he used the lytic enzymes derived from viruses as a laboratory reagent for many years while studying Group A Streptococci before it dawned on him that the enzymes could be used for therapeutic purposes. He first purified the enzymes as a graduate student in 1967 using commercial cloning and expression kits. He did not think to market the enzymes at that time because bacterial resistance against antibiotics was not a problem.
“I’ve been working on Group A Strep for most of my career and I used [the viral enzymes] as a means to extract proteins from Strep,” Fischetti said. “People knew that these enzymes were being used by the virus, but no one’s ever used them for therapeutic purposes.”
Depending on the type of infection involved, the therapeutic enzymes are administered either through a nasal or oral spray or intravenously, Fischetti said.
Therapeutic enzymes against anthrax are currently in the first phases of clinical trial, and researchers are working on starting clinical trials to test the other enzymes, he added.
This approach “gets around the typical problem which is drug resistance which occurs with antibiotics,” said Charles Daley, an associate professor and director of the Tuberculosis Training Center at the University of California San Francisco. “It’s a very intriguing approach to therapeutics.”
Both Daley and Fischetti noted that it would take much longer for pathogens to be able to develop genetic machinery to avoid lysis than it would for the pathogen to be able to combat the disruption in intracellular pathway machinery that antibiotics typically employ.
Daley cautioned that the enzymes would have to be tested to make sure that they not only work, but are safe.
“People tend to react to foreign proteins,” said Daley. “And then there is the problem of can you get [the enzyme administered] more than once, because you can develop antibodies to these proteins and if you get it again, you could have a severe allergic reaction.”
Fischetti said that in the early phase of clinical trials, lytic enzymes against anthrax have not found any other substrate to bind to other than target anthrax pathogens.
Fischetti and his research group have been issued 19 patents for their therapeutic enzymes. They plan to collaborate with a small start-up company to develop pharmaceutical applications.
“I think the potential to generate revenue from this is good,” said Fischetti. “If you can use it in hospitals, nursing homes, day care centers, places like that — those are very large markets. And laboratory kits are also fairly large markets.”
In the future, it will be challenging to develop bacteriophage-derived lytic enzymes against gram negative pathogens, such as Salmonella and Escherichia coli which have an outer membrane that needs to be broken, in addition to an inner membrane, Fischetti said.