A team of scientists at The Rockefeller University in New York City has developed an anti-infective therapy that combines a tool produced by bacteria-killing viruses with the disease-fighting capabilities of the human immune system, a combination they hope could be a potent weapon in the fight against antibiotic-resistant pathogens.
The work stems from research that Vincent Fischetti, PhD, and his colleagues at Rockefeller have been doing with bacteriophages, or phages—the ubiquitous viruses found in nature that infect and then destroy bacteria using enzymes called lysins, which cut through the bacterial cell wall, allowing progeny phages to escape their bacterial host and seek their next victim.
Since 2001, Fischetti has been experimenting with phage lysins, testing them against gram-positive bacterial pathogens in lab experiments and mouse models. These experiments have shown that when lysins are administered to bacterial pathogens in culture dishes and infected mice, the enzymes seek out and destroy the bacterial cells from the outside. So far, the approach has proven effective in experiments against nearly all gram-positive bacteria.
Possible weapon against MRSA
Now, in a study published yesterday in the Proceedings of the National Academy of Sciences, Fischetti and his colleagues describe a new iteration of this research, in which they've combined lysins with elements of antibodies, the proteins produced by the human immune system to fight invasive diseases.
In experiments on mouse models infected with strains of Staphylococcus aureus, they demonstrated that three different versions of these molecules, which they dubbed lysibodies, could latch onto the bad bacteria and neutralize them, thereby protecting the mice from infection. Most notably, the approach proved effective against methicillin-resistant S aureus (MRSA), a common antibiotic-resistant threat in hospitals and community settings.
In one of the models, Fischetti and his team injected a group of mice with lysibodies, then a day later gave them a strain of MRSA. Four days later, they harvested the kidneys of the mice that had been given lysibodies and found that most of them were devoid of MRSA infection, while the kidneys from a control group had a high bacterial load. In the other model, the researchers again gave lysibodies to a group of mice, then injected a much more virulent MRSA strain directly into their blood.
"The control animals died within 24 hours, whereas the animals that received the lysibodies were protected," Fischetti, a professor of immunology, virology, and microbiology at The Rockefeller University, told CIDRAP News. "So, in two animal models, we showed that we could protect animals against two different strains of MRSA."
The lysibodies also worked against several strains of MRSA in culture dishes. In addition, Fischetti and his colleagues showed that a lysibody created with lysins produced by bacteria was effective against MRSA. These lysins, called autolysins, are enzymes that bacteria use to break down cell walls during growth and division.
An antibody 'nature can't make'
Fischetti said that this approach is a product of the years he's spent working with phage lysins, antibodies, and vaccines, work that led him to the realization that the ability of lysins to bind to carbohydrates—a major component of the bacterial cell wall—could be used not just to kill bad bacteria but also could be harnessed to activate the immune system against bacterial pathogens like S aureus. That's because lysins, in effect, compensate for one of the weaknesses of the immune system—that it's not good at producing antibodies that target carbohydrates on the cell walls of bacteria.
"Our bodies are designed to make antibodies against proteins on the surface of the bacteria, but we don't make good antibodies to carbohydrates," Fischetti said. This is one of the reasons why little progress has been made in developing vaccines or therapeutic antibodies to combat MRSA infections.
"But in this trick, the bacteriophage lysins target the carbohydrate, and it binds to that carbohydrate at a high affinity," he explained.
With this problem solved, Fischetti and his team then attached the lysins to a segment of human antibodies known as the Fc (fragmented crystallizable) region, which communicates with the immune system. By combing the binding function of lysins with the component of antibodies that engages the body's immune response, Fischetti said, "now you've created an antibody that nature can't make."
And while phage lysins would mostly be used in patients who are immunocompromised (in combination with antibiotics), lysibodies could be used in otherwise healthy individuals with bacterial infections, providing short-lived protection against the bacterial invader.
"So this in a sense is a way to get antibodies against staphylococci that you can add passively to an individual that's infected, and cure that individual by the use of their normal immune system," he added.
Resistance has not been an issue
While the current study demonstrated that this approach was effective against S aureus and MRSA infections in mice, the research has wider implications, since nearly all types of bacteria can be targeted by lysins. "It's a platform," Fischetti said. "There are phage lysins against virtually every bacteria that's out there, so you could do the same thing for any organism."
And with antibiotic resistance becoming an urgent public health threat, another potential benefit of lysibody therapy is that to this point, bacterial resistance to phage lysins hasn't been observed.
"We have not seen resistance yet," Fischetti said. "That's not to say it won't occur, but it's a much rarer event."
In addition, lysins are narrow-spectrum anti-infectives that "only kill the organisms you wish to kill, without collateral damage." In other words, they leave the body's beneficial bacteria alone.
The Tri-Institutional Therapeutics Discovery Institute, a drug discovery partnership between Rockefeller, Weill Cornell Medicine, and Memorial Sloan Kettering Cancer Center is now manufacturing lysibodies for further testing. Fischetti said that the next step for lysibody therapy is to test it for toxicity in animal models. If lysibodies prove to be safe in animals, phase 1 clinical trials will follow.
Apr 20 Proc Natl Acad Sci USA abstract