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Public Information on Grants associated with NYSBC_ Grant Number: 2R01AI011822-34A1Project Title: Properties of streptococcal M protein PI Information: Name Email Title FISCHETTI, VINCENT A. vaf@rockefeller.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): Our main objective is to develop methods to protect against streptococcal infections in particular and gram-positive infections in general. Group A streptococcal-associated disease (pharyngitis, rheumatic fever, necrotizing fasciitis, impetigo, and scarlet fever, to name a few) affects millions of people, particularly children, worldwide. In developing countries, rheumatic heart disease is the major cause of heart damage in the school-age population. The severity of streptococcal diseases provides the impetus to develop novel methods to both prevent and treat these infections. Using a mucosal vaccine approach we have been successful in achieving cross-protection against heterologous streptococcal serotypes in a mouse model using the conserved region of the streptococcal M protein as the antigen. This approach circumvents the need to prepare type- specific antigens directed to the >120 streptococcal M serotypes. Furthermore, since the only reservoir for group A streptococci is the human pharynx, we have used a model system to successfully decolonized the oral cavity of mice of colonizing group A streptococci using a specific phage lytic enzyme. We hope to use this approach to reduce the bacterial burden in the human population and thus reduce disease. The experiments outlined in this proposal will expand these findings to develop both a new generation streptococcal vaccine and a prophylactic treatment to prevent streptococcal infections. In addition, during our studies, we identified a novel glycosylated enzyme in group A streptococci that is responsible for both attachment of surface proteins and cell wall assembly. This novel molecule is not ribosomally synthesized and as such we wish to determine its method of assembly. Since this glycoprotein is also found in other gram- positive bacteria (i.e., staphylococci and pneumococci) an understanding of its biosynthesis should offer novel targets for antibiotic development against these and perhaps other bacterial pathogens. The complete or partial M protein has not yet been crystallized. To better understand the details of the M protein structure and its multifunctional capacity, we will collaborate to solve the crystal structure of the biologically active N- and C-terminal halves of the molecule. Since many surface proteins on gram-positive bacteria are extended coiled-coil structures of modular design, structural data for the M molecule will allow for a better understanding of other surface proteins on gram-positives. In summary, our continued studies on gram-positive pathogenic bacteria over the >30 years of this grant has revealed new information regarding these pathogens enabling new strategies for their control; this application will continue in this direction. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: ROCKEFELLER UNIVERSITY NEW YORK, NY 100656399 Fiscal Year: 2008 Department: BACTERIAL PATHOGENESIS & IMMUNOLOGY LAB Project Start: 01-APR-1997 Project End: 31-MAY-2012 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: BACP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| > > | Grant Number: 5R01AI057472-05 Project Title: Isolaton of new phage enzymes to kill B. anthracis PI Information: Name Email Title FISCHETTI, VINCENT A. vaf@rockefeller.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): Our current defense against Bacillus anthracis, and other bacterial bioweapons, is based primarily on the use of antibiotic therapies. This plan is flawed considering the possibility that the bacteria used in such weapons may express naturally occurring or engineered resistances to current therapeutic or prophylactic antibiotics. For this reason we are currently developing a novel class of antibacterial agents. Our system is based on the use of phage lysins to provide a rapid and specific killing action against bacterial pathogens of interest, in particular B. anthracis. In addition to offering a previously unavailable method of bacterial killing, phage lysins are primarily attractive in that bacterial resistance to their action cannot be detected, even after extensive attempts. Our laboratory is the first to use these enzymes in their purified form to kill colonizing pathogenic bacteria on mucous membrane surfaces and in blood. The enzymes are specific for the species or strain from which the enzymes were derived, indicating that these enzymes may be used for targeted killing of only the pathogenic bacterium with little to no effect on normal flora bacteria. During these studies we discovered that enzymes with two different specificities for cell wall bonds (i.e., amidase and muramidase) have a synergistic effect in their killing capacity. In our studies with the PlyG? phage enzyme from the gamma phage that is specific for B. anthracis, we show that this enzyme is able to kill anthrax bacilli in vitro, reducing 108 bacteria to sterility in two minutes. In vivo, we are able to protect animals from lethal challenge with both a closely related bacillus to B. anthracis as well as B. anthracis. Because of the synergistic effects in these enzymes, this application is designed to identify and develop a combination of enzymes for B. anthracis that attack the four different bonds in the bacillus cell wall. This will ensure a more efficient killing action as well as reduce the possibility of the development of resistance to these enzymes. Phage enzymes will be isolated from phage found in the environment and phage lysogenizing B. anthracis. These enzymes will then be characterized as to their specificity, purified and used in both in vitro and in vivo systems to determine efficacy. Because these enzymes may be an important line of defense against an attack with drug-resistant B. anthracis, having a number of enzymes at our disposal may allow for better decisions as to their use if necessary. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: Bacillus anthracis, antibacterial agent, bacteriolysis, drug design /synthesis /production, enzyme bacterial virus, cell wall, drug resistance, enzyme activity, enzyme mechanism, mucosa, proteoglycan chromatography, laboratory mouse Institution: ROCKEFELLER UNIVERSITY NEW YORK, NY 100656399 Fiscal Year: 2008 Department: BACTERIAL PATHOGENESIS & IMMUNOLOGY LAB Project Start: 01-JUN-2004 Project End: 31-MAY-2009 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: ZRG1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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