Human-Germ Hybrid Fights Drug-Resistant Bacteria

Scanning electron micrograph of human neutrophil ingesting MRSA bacteria. (National Institute of Allergy and Infectious Diseases)

(CN) – Human-germ hybrid molecules engineered by scientists to attack drug-resistant bacteria give new meaning to the Sanskrit proverb “the enemy of my enemy is my friend.”

Inspired by the deadly – yet effective – nature of viruses, a team of researchers has created a new weapon against disease-causing bacteria, which are increasingly becoming resistant to conventional antibiotics.

The team engineered molecules that can target specific carbohydrate molecules that appear on the surfaces of bacterial cells, a process that viruses typically do much better than the human immune system.

“Bacteria-infecting viruses have molecules that recognize and tightly bind to these common components of the bacterial cell’s surface that the human immune system largely misses,” said lead author Vincent A. Fischetti. “We have co-opted these molecules, and we’ve put them to work helping the human immune system fight off microbial pathogens.”

In tests on mice, Fischetti’s team used these molecules to successfully treat life-threatening MRSA infections – a bacterium that is resistant to standard antibiotics. The results of these experiments suggest the researchers might have developed a new tool for fighting such superbugs.

The approach capitalizes on the ability of viruses to latch onto and cut through the walls of bacteria, which kills these cells in the process. These viral predators use molecular snippers, called lysins, which bind to specific carbohydrates in cell walls.

The human immune system is not so effective. While it can produce antibodies that are good at binding to proteins on bacterial cells, which tags the bacteria for destruction by immune cells, the immune system is less adept at dealing with carbs.

But lysins and antibodies do share some structural similarities, which gave the researchers an idea.

“Both antibodies and lysins have two discrete components. They both have a part that binds their respective target, but whereas the second component of lysins cuts the bacterial cell wall, in antibodies it coordinates an immune response,” said co-author Assaf Raz, who led the experiments.

“This made it possible for us to mix and match, combining the viral piece responsible for latching onto a carbohydrate with the part of the antibody that tells immune cells how to respond.”

The team also borrowed an attribute of bacteria.

Like viruses, bacteria make a carbohydrate-binding and cutting molecule, which they use to alter their own cell walls while growing. As they did with the lysins, the team combined the binding region from one of these remodeling enzymes with a piece of human antibody.

Calling their creation “lysibodies,” the team made three types: two adapted from viruses and one from bacteria. The researchers then tested the lysibodies on strains of drug-resistant staph, including MRSA.

In their experiments on rats, the team found that the lysibodies successfully attached to carbs on the surface of staph and triggered immune cells to destroy them. Since different types of related bacteria have the same types of carbs, the lysibodies were able to grab onto a variety of strains of staph.

The lysibodies were also effective at stifling MRSA. Treatment with one of the lysibodies greatly improved the survival of MRSA-infected mice, while another type was able to help prevent severe kidney infections in the rodent subjects.

As nearly all bacteria may be infected by lysin-producing viruses, the new approach could be used against several disease bacteria.

“Based on our results, it may be possible to use not just lysins, but any molecule with a high affinity toward a target on any pathogen – be it virus, parasite, or fungus – to create hybrid molecules,” Fischetti said. “This approach could make it possible to develop a new class of immune-boosting therapies for infectious diseases.”

The Tri-Institutional Therapeutics Discovery Institute, a partnership created to accelerate early-stage drug discovery, is already manufacturing lysibodies and has plans to begin testing their safety.

The team shared their findings in the current edition of the Proceedings for the National Academy of Sciences.

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