SYNTHETIC ANTAGONISTS OF THE PSEUDOMONAS AUTOINDUCER

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Pseudomonas aeruginosa persists as a serious pathogen infecting the most seriously ill, including cystic fibrosis patients. The tenacious survival of P. aeruginosa, as well as many others of the highly necrotic and toxic effects from P. aeruginosa infections, rely on exoproducts called virulence factors. Expression of virulence factors is regulated by a quorum-sensing mechanism that deploys these factors only when a sufficient concentration of bacteria can make a concerted attack on the host. A master regulatory transcription factor, LasR, controls a number of the individual genes; LasR is activated by a small molecule autoinducer, N-(3- oxo-dodecanoyl)-L-homoserine lactone (PAI-1). A second regulator/autoinducer complex, RHlR and its cognate agonist N-butyryl-L- homoserine lactone (PAI-2), is also a part of the P. aeruginosa virulence factor cascade. We plan to develop antagonists to PAI-1 and PAI-2 that produce the avirulent condition observed in lasl and rhll mutants. Since modifications of the 3-keto group diminishes Pal-1 activity, we will pursue the hypothesis that the beta-ketoamide structure plays a critical role for the Pseudomonas LasR autoinduce. In Phase 1 we will focus primarily on PAl-1 to determine the tautomeric form of the beta-ketoamide in its bioactive state, and we will put in place the appropriate chemistry and biological assays. Proposed commercial applications: A small-molecule antagonist of the autoinducer would target the destructive virulence factors of Pseudomonas, and be useful in treating nosocomial infections and chronic infections seen in cystic fibrosis patients. It would decrease or abolish the damage done during the early stages of infection, and in all stages, disrupt the formation of the biofilm, thereby rendering the pathogen significantly more vulnerable to antibiotic therapy. The current estimate of suitable cases for such therapy could easily approach 100,000 in the U.S.