Investigator: Susan Meschwitz, Salve Regina University

Mentor: David Rowley, University of Rhode Island

Scientific Theme: Molecular Toxicology

Abstract: The misuse and abuse of antibiotics in pharmacotherapy have led to the development of widespread resistance in the target organism.  This is especially true in the notoriously difficult to treat, often multidrug resistant pathogen, Pseudomonas aeruginosa. The failure of existing antibiotics to control infection makes it crucial to find alternatives to currently available drugs, particularly ones that do not impose harsh selective pressure for bacteria to develop resistance.  Many pathogenic bacteria rely on a communication system knows as quorum sensing (QS) to regulate virulence factors necessary for infection of a host. Quorum sensing is controlled by small molecules called autoinducers to coordinate collective behaviors.  The reliance of quorum sensing bacteria upon small molecule autoinducers to coordinate collective behaviors. The reliance of quorum sensing bacteria upon small molecule autoinducers affords the opportunity to investigate and inhibit quorum sensing systems at the molecular level and provides a potential route to novel anti-inefective therapeutics. Our long- term objective is to design and synthesize molecules capable of modulating quorum sensing. Blocking this communication system could potentially prevent bacterial pathogenesis with a lower risk of resistance. Using the structure of the native Pseudomonas quinolone signal (PQS) as a template, we intend to design and synthesize a library of synthetic analogues in order to investigte the potential of these compounds to intercept quorum sensing regulated gene expression in P. aeruginosa. The compounds synthesized during this project will be evaluated for their biological activity with respect to quorum sensing with the collaboration of Dr. David Rowley at the University of Rhode Island and Dr. Michael Givskov at the University of Copenhagen. In addition to serving as valuable tools in the study of quorum sensing, the synthesized compounds are also anticipated to provide potential new leads in the development of antiinfective agents.

Human Health Relevance: The increasing use of antibiotics in humans, animals, and agriculture has resulted in many microbes developing resistance to these powerful drugs. Future effective treatment will require the use of new therapeutic agents with different mechanisms of action. The goal of this proposal is to design and synthesize potentially novel therapeutics for the treatment of certain bacterial infections.