Staphylococcus aureus is a major human pathogen causing over 500,000 nosocomial infections per year. Staphylococci cause diseases via the production of toxins, known as virulence factors. Recent work indicates that the expression of virulence factors in S. aureus is controlled by an autocrine global regulatory system, agr. The bacteria secrete into the medium a protein (termed RNAIII Activating Protein, or RAP) that upregulates the sets of genes (global regulon) which controls virulence, thus leading to toxin synthesis. Anti-RAP antibodies, inhibit toxin synthesis in vitro. A non-pathogenic mutant strain of S. aureus produces a pentapeptide (termed RNAIII Inhibiting Peptide, or RIP) that directly inhibits bacterial toxin production, suggesting that RIP may serve as a direct suppressor of infections caused by staphylococci. The overall goal of this project is to develop RIP or a suitable analog as an inhibitor of exotoxin synthesis to suppress staphylococcal infections. To this end Phase I seeks to establish the RIP concept in vivo using suitable animal models and to develop a reporter assay to screen RIP mimetics. In Phase II a combination of NMR structure, combinatorial structure-activity studies and screening using the assay will be used to select a lead compound. This will be followed by animal pharmacokinetics, toxicology and efficacy studies in preparation for an IND. PROPOSED COMMERCIAL APPLICATIONS: Staphylococcus aureus is a major human pathogen. A new means to curtail this pathogen will have significant market opportunities.