Dr. Fischetti works with gram-positive bacteria, like streptococci, that do not contain a second cell membrane outside of the cell wall. By examining how these bacteria attach themselves to cells, the Fischetti lab is working to develop means to prevent infection at the site where bacteria first encounter their hosts: on the human mucous membranes that line the nose and throat. The lab’s work focuses on inducing immune responses on those membranes to help prevent bacteria from taking hold and replicating.

A key area of this research involves lytic enzymes from bacteriophage. Bacteriophage (or phage) are viruses that infect bacteria in order to produce viral progeny. Once the virus has replicated, it releases its progeny by producing an enzyme that degrades the bacterial cell wall, causing the bacteria to explode. Dr. Fischetti’s lab recombinantly produced three of these enzymes, called phage lytic enzymes, that infect three different bacteria — Streptococcus pyogenes, Streptococcus pneumoniae and Bacillus anthracis — and have used these proteins to destroy their respective bacteria in animal models of disease. The enzymes are extremely potent: only a very small amount is needed to destroy millions of organisms within seconds of contact, and Dr. Fischetti’s studies have shown that when small amounts of the enzymes are administered to mice that had intentionally been infected with these bacteria, the disease-causing bacteria are destroyed.

Dr. Fischetti’s lab sees lytic enzymes as a nonantibiotic method to control the bacteria that normally cause infection. One benefit of this treatment is that these enzymes are highly specific, only killing a specific species of bacteria; unlike antibiotic drugs, they do not harm other bacteria in the host, many of which are beneficial. Since nearly all bacteria have phage that infect them, phage lytic enzymes may be developed for almost any disease-causing bacteria. Current work in the lab is focused on isolating lytic enzymes for all the major pathogenic bacteria.

A second research project in the Fischetti lab is aimed at understanding the process by which proteins become attached to the cell surface of bacteria, and how this process can be interrupted with small molecules. Bacteria use their surface molecules to invade tissues, and knowledge of the anchoring process they use could lead to strategies to prevent attachment of the proteins to the cell and block infection. The M protein is the major virulence factor of group A streptococci because of its ability to impede attack by human immune cells. Analysis of this molecule by Dr. Fischetti’s lab shows that the region attached to the cell surface is highly conserved in gram-positive bacteria, indicating that the mechanism for anchoring surface proteins in bacteria is also conserved. Thus, a molecule that blocks surface protein attachment will be broadly applicable to different gram-positive bacteria.

Dr. Fischetti’s lab has shown that active proteins fused to the common anchor region of the M protein can be used to deliver the molecules to the surface of gram-positive bacteria to be used as a vaccine. A vaccine that employs this approach could be used against a variety of harmful pathogens, and is currently being tested in clinical trials. Dr. Fischetti 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.

CAREER

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 University 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.