Heads of Laboratories
Infections by Gram-positive bacteria are a major cause of morbidity and mortality worldwide. The Fischetti lab is working to understand the earliest events that occur when Gram-positive bacteria interact with human tissues and cause disease. His research is aimed at developing strategies to interfere with these events, such as vaccines to induce a mucosal immune response, and using phage lytic enzymes to both remove colonizing pathogenic bacteria to prevent infection and treat established infections.
Dr. Fischetti works with Gram-positive bacteria, such as streptococci, that do not contain a second cell membrane outside of the cell wall. In the fight against infectious disease, Dr. Fischetti investigates two non-antibiotic treatment strategies. This two-pronged approach involves blocking bacteria from attaching to cells and exploring the use of phage lytic enzymes to remove pathogenic bacteria once they have colonized in the host.
To infect their host, bacteria use their surface molecules to attach and invade human tissues, particularly those that line the nose and throat. Knowledge of the process bacteria use to anchor these molecules in their cell wall could lead to strategies to prevent infection. The M protein is a surface protein that is the major virulence factor of group A streptococci because of its ability to impede attack by human white blood cells. Analysis of this molecule by Dr. 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 their surface proteins, a molecule that blocks surface protein attachment will be broadly applicable to different Gram-positive bacteria.
Dr. Fischetti’s lab has also identified a membrane-associated enzyme responsible for cleaving the highly conserved anchor region of surface proteins. Inhibition of this enzyme prevents both cell wall assembly and the proper attachment of most surface proteins, resulting in nearly naked bacteria. Studies are under way to further define the role of this enzyme in cell wall assembly and the protein attachment process to identify inhibitors that may be used as a new class of antibiotic.
As new antibiotics are proving futile against resistant strains of bacteria, the Fischetti lab has developed a method to identify novel targets in bacterial cells that have proven to produce “resistance-proof” antibiotics. Dr. Fischetti’s lab has also recombinantly produced phage lysins that will kill the major Gram-positive pathogens — Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecalis and Bacillus anthracis — and has used these enzymes to destroy their respective bacteria in animal models of disease. The enzymes are extremely potent; only very small amounts are needed to destroy millions of organisms within seconds of contact. They are also highly specific and, unlike antibiotics, only kill the disease-causing bacteria without harming the beneficial bacteria.
Dr. Fischetti’s studies have shown that when small amounts of the phage lysins are administered to mice that have intentionally been infected with these bacteria, the disease-causing bacteria are rapidly destroyed. In an animal model of pneumococcus pneumonia, Dr. Fischetti and his collaborators have shown that systemic administration of the phage enzyme Cpl-1 can rescue mice infected with the pathogen and completely reverse lung tissue damage if given within 24 hours postinfection. Fischetti and his colleagues showed that when the enzyme is delivered to the brain of mice with pneumococcal meningitis, it effectively removes the organisms from the site. The lab has also shown that by removing colonizing S. pneumoniae from the nose of mice, they could completely prevent secondary ear infections triggered by influenza. This lysin technology has been licensed and is expected to be ready for human trials in early 2013.
Using lytic enzymes as a tool, Dr. Fischetti’s lab developed a method of drilling through the thick cell walls of Gram-positive bacteria while keeping them intact. The technique enabled the Fischetti lab to access the bacterial cytoplasm with labeled antibodies to study intracellular molecules that were previously inaccessible.
Dr. Fischetti grew up in New York City, receiving his B.S. in bacteriology from Wagner College in 1962 and his M.S. in microbiology from Long Island University in 1967. He received his Ph.D. in microbiology from New York University in 1970. Dr. Fischetti came to Rockefeller as a postdoc in 1970 and became assistant professor in 1973, associate professor in 1978 and professor in 1990. In 1987 Dr. Fischetti received a 10-year National Institutes of Health MERIT Award that was renewed in 1997.
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