NOVEL THERAPY FOR STAPHYLOCOCCAL INFECTION

Panorama Research, Inc., Sunnyvale CA

Investigators

Abstract

The emergence of antibiotic-resistant Staphylococcus aureus has created an urgent need for new therapeutic approaches to treat the variety of diseases caused by this common pathogen. S. aureus damages host tissues by the secretion of a variety of toxic exomolecules know as virulence factors. The expression of these factors is controlled by an autocrine regulatory system whereby bacteria secrete autoinducing pheromone peptides that act on the cell to upregulate expression of the set of genes encoding virulence factors. This proposal is based on the serendipitous discovery of a modified peptide contaminating a batch of synthetic pheromone peptide based on the sequence of a non-pathogenic strain of Staphylococcus. This peptide, called virulence inhibitory factor (VIF), inhibited synthesis of alpha toxin and toxic shock syndrome toxin in all Staphylococcal strains tested. The goal of this proposal is to purify VIF, determine its structure, synthesize it, and test it in vitro for inhibition of virulence factor production. Since VIF does not inhibit bacterial growth there is a reduced risk to promote emergence of resistant strains. This novel therapeutic approach has promise in the treatment of antibiotic resistant Staphylococci. PROPOSED COMMERCIAL APPLICATION: Due to the emergence of drug-resistant strains of Staphylococci, many infections are not treatable with conventional antibiotics. The pathogenesis of Staph. infections depends on the production of virulence factors that promote bacterial colonization and are toxic to host tissues. The present application proposes to develop a novel drug that inhibits production of virulence factors and should be therapeutic to antibiotic resistant Staph. PROPOSED COMMERCIAL APPLICATION: The overall goal of this project is to hasten the development of cell replacement therapies for degenerative disease and injury. Human stem cell lines promise to provide all of the cell types required for transplantation. But first there is a need to control and characterize stem cell differentiation in culture. The goal of the Phase I project is to use microarray technology to identify "expression profiles" that uniquely identify differentiated cell types. As a model system we will use the clinically relevant human Ntera-2 teratocarcinoma cell line which differentiates into neurons. The project has two specific aims: Aim 1: the expression pattern of 9000 genes will be determined for both the Ntera-2 precursors and the neurons. From the group of 100-200 expected differentially expressed genes, we will designate a subset of 10 to 20 genes as an "expression profile panel." Aim 2: clinically applicable RT-PCR methods will be developed for the rapid quantification of the expression profile panel genes. In Phase II of the project, the technologies will be refined for clinical assays and extended to other types of stem cells. This work will provide the basis for quality control and purification processes for generating homogeneous human cell populations for cell replacement therapies. PROPOSED COMMERCIAL APPLICATION: The research funded by this grant will be used to develop purification and quality control procedures for application to the transplantation of differentiated cells derived from stem cell precursors. These procedures will be commercialized by licensing them and providing them to healthcare providers and corporations that produce cells for transplantation.