INVESTIGATOR: Susan Meschwitz, Salve Regina University
THEME: Environmental Health Sciences

ABSTRACT: Traditional therapeutics to treat bacterial infections have given rise to multi-drug resistant pathogens, which pose a major threat to human and environmental health. Many bacteria found in the environment and in chronic infections exist in highly structured multi-cellular communities known as biofilms, and the high population densities and the proximity of cells in these biofilms are particularly susceptible to antibiotic pollution and the spread of antibiotic resistance. Furthermore, the biofilm mode of growth has been implicated in the protection of human pathogens against the host immune defense and enhanced tolerance against conventional antibiotics.  Thus, the failure of existing antibiotics to control infection makes it crucial to find alternative drugs, particularly ones that do not impose selective pressure for development of resistance. Pathogenic bacteria rely on chemical communication, known as quorum sensing (QS), to control production of toxic virulence factors necessary for infection and for the formation of biofilm. Hence, molecules that disrupt QS are viewed as viable alternatives to traditional antibiotics. We have recently identified three molecular scaffolds with promising inhibition of QS- controlled bacterial phenotypes. In the next phase of this work, we will test the most active analog from each of our three molecular scaffolds for the ability to inhibit virulence factor production and biofilm formation in the clinically relevant human pathogen Pseudomonas aeruginosa. In addition to serving as valuable tools in the study of quorum sensing, these compounds are also anticipated to provide potential new leads in the development of anti-infective agents and in the prevention of biofilm formation.

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, synthesize, and test potentially novel therapeutics for the treatment of certain bacterial infections.