The opportunistic human pathogen, Pseudomonas aeruginosa, utilizes acyl-homoserine lactones (acyI-HSL) as quorum sensing autoinducers to activate the expression of numerous virulence genes. Some virulence factors are directly toxic to host tissues while others promote formation of biofilms that then confer resistance to antibiotics in organisms enmeshed in these structures. This is a serious problem for cystic fibrosis patients who often develop chronic lung infections with P. aeruginosa that persist despite aggressive antibiotic therapy. Recent concern for the selection of antibiotic resistant bacteria has stimulated interest in the development of novel therapeutics that inhibit virulence factor production in various kinds of bacteria. The goal of this application is to develop novel small molecules that inhibit acyl-HSL quorum sensing in P. aeruginosa and thereby decrease production of virulence factors. Lead pyrrinone and furanone compounds having the desired activity have already been identified. Additional structurally related molecules will be synthesized and tested in vitro. The results of these assays will reveal which compounds are the most potent inhibitors of quorum sensing and virulence factor production. Active compounds will also be tested for inhibition of bacteria growth. Drugs that are not toxic to the bacteria may decrease the likely-hood for the selection of resistant bacteria variants. Drugs that show the best activity in in vitro assays will also be tested in a simple mouse model of P. aeruginosa lung infection. Future Phase II studies will test the lead drug candidate in animal models of Pseudomonas infection in lung, sepsis and burns. These studies may lead to the development of a new anti-Pseudomonas drug with a unique mechanism of action that may be especially useful for immunocompromised patients infected with antibiotic-resistant organisms.
