Heads of Laboratories
Laboratory of Bacterial Pathogenesis and Immunology
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 enzymes derived from bacteria-killing viruses known as phage to prevent and treat infections. He has also identified novel targets for antibiotic development.
Dr. 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 anti-infectives and the use of phage lytic enzymes to both prevent infection and remove pathogenic bacteria from infected tissues.
Dr. Fischetti’s lab uses recombinantly produced phage lysins that will kill the major gram-positive and gram-negative pathogens — 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.
Dr. 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 pneumococcus pneumonia, Dr. 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 postinfection. Experiments involving pneumococcal meningitis and secondary ear infections caused by S. pneumonia returned similar results. This lysin technology has been licensed and is currently in human clinical trials.
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.
As new antibiotics are proving futile against resistant strains of bacteria, the Fischetti lab has developed a method using phage lysins to identify weak points in bacterial cells that can be exploited for antibiotic development. Using this approach, the Fischetti lab has identified a novel target, the enzyme 2-epimerase, involved in cell wall biosynthesis and critical for bacterial survival. A novel inhibitor based on this target, Epimerox, was found to protect animals from lethal infection, and no bacterial resistance has been found to Epimerox.
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 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 Dr. Fischetti’s lab shows 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.
B.S. in bacteriology, 1962
M.S. in microbiology, 1967
Long Island University
Ph.D. in microbiology, 1970
New York University
The Rockefeller University, 1970–1972
Albert Einstein College of Medicine, 1972–1973
Assistant Professor, 1973–1978
Associate Professor, 1978–1990
The Rockefeller University
National Institutes of Health MERIT Award, 1987, 1997
Utter, B. et al. Beyond the chromosome: the prevalence of unique extra-chromosomal bacteriophages with integrated virulence genes in pathogenic Staphylococcus aureus. PLoS One 9, e100502 (2015).
Gilmer, D.B. et al. Novel bacteriophage lysin with broad lytic activity protects against mixed infection by Streptococcus pyogenes and methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 57, 2743–2750 (2013).
Schuch, R. et al. Use of a bacteriophage lysin to identify a novel target for antimicrobial development. PLoS One 8, e60754 (2013).
Raz, A. et al. Cellular aspects of the distinct M protein and SfbI anchoring pathways in Streptococcus pyogenes. Mol. Microbiol. 84, 631–647 (2012).
Daniel, A. et al. Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 54, 1603–1612 (2010).