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The Fischetti lab exploits the evolution of bacteria-killing viruses, known as phages, to develop new ways to prevent and treat bacterial infections. This strategy has revealed bacteria-killing enzymes and novel immunotherapies that can overcome antibiotic-resistant bacteria.

Fischetti works with both gram-positive and gram-negative bacteria, such as streptococci, staphylococci, anthrax, and acinetobacter, to develop unique treatment strategies to prevent infection. His approach involves novel immunotherapies and the use of phage lytic enzymes to both prevent infection and remove pathogenic bacteria from infected tissues.

Fischetti’s lab uses recombinantly produced phage lysins that will kill the major gram-positive and gram-negative pathogens including Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, Clostridium difficile, Bacillus anthracis, and Acinetobacter baumannii. The enzymes are extremely potent; micrograms can destroy millions of organisms within seconds. They are also highly specific and, unlike antibiotics, only kill the disease-causing bacteria, without harming the beneficial bacteria.

Fischetti’s studies have shown that when small amounts of phage lysins are administered to infected mice, disease-causing bacteria are rapidly destroyed. In an animal model of pneumococcal pneumonia, Fischetti and his collaborators have shown that systemic administration of the phage enzyme Cpl-1 can rescue infected mice and completely reverse lung tissue damage if given within 24 hours post-infection. Similarly, experiments involving antibiotic-resistant S. aureus causing serious bacteremia in mice returned similar results after treatment with a staphylococcal-specific lysin. This lysin technology has been licensed and is currently in human clinical trials.

Using lytic enzymes as a tool, Fischetti’s lab developed a method of drilling through the thick cell walls of gram-positive bacteria while keeping the cells intact. The technique enabled the researchers to access the bacterial cytoplasm with labeled antibodies to study intracellular molecules that were previously inaccessible.

As a result of the high variability and plasticity of S. aureus, vaccine development has been challenging and has yet to be accomplished. Using the high-affinity binding domain of phage lysins directed to S. aureus, the Fischetti lab has successfully developed fusion immunoglobulins (called lysibodies) with the capacity to bind to the common cell wall of all Staphylococci, resulting in efficient phagocytic killing by human white blood cells. Lysibodies may be used to boost the immune response of Staphylococcus-infected patients.

Because bacteria use their surface molecules to attack and invade human tissues, a better understanding of how they anchor these molecules in their cell walls could lead to new strategies to prevent infection. The M surface protein is the major virulence factor of group A streptococci because of its ability to impede human white blood cells. Analysis by Fischetti’s lab shows that the region used to attach the M protein to the streptococcal cell surface is highly conserved in all gram-positive bacteria, indicating that the mechanism for anchoring surface proteins in bacteria is also conserved. Since bacteria cannot cause infection without surface proteins, a molecule that blocks surface protein attachment would be broadly applicable to different gram-positive bacteria.