Abstract:Bacterial infections are a leading cause of death
in children and the elderly in the United States. The widespread and
sometimes inappropriate use of antibiotics to treat bacterial infections
have contributed to the rapid development of antibiotic resistance in
bacterial populations. Many pathogenic bacteria rely on a communication
system known as quorum sensing to regulate virulence factors necessary
for infection of a host. This quorum sensing communication system is
controlled by small molecules called autoinducers to coordinate
collective behaviors. This reliance of quorum sensing bacteria upon
small molecule autoinducers offers the opportunity to investigate and
inhibit quorum sensing systems at the molecular level and provides a
potential route to novel antibacterial therapeutics. Our long term
objective is to synthesize molecules capable of modulating quorum
sensing. To this end, we have three molecular targets, which will serve
as the specific aims of our proposal: 1) We will synthesize phevalin, a
known regulator of virulence factor expression, and several synthetic
derivatives of phevalin; 2) Several phenylethylamides, which are
secondary metabolites isolated from marine gram-positive bacterium,
capable of quenching quorum sensing and are structurally related to
phevalin, will also be synthesized and tested; 3) We will synthesize N-acyl
derivatives of cycloserine, the FDA approved antibiotic for the
treatment of tuberculosis. These derivatives will be structurally
similar to the N-acyl homoserine lactones (AHLs), the most studied and
understood autoinducers of quorum sensing. All of the synthetic targets
will be tested for their effect on quorum sensing in the laboratory of
David Rowley at the University of Rhode Island. The molecules
synthesized during this project are anticipated to serve as valuable
tools in the study of quorum sensing and provide potential new leads in
the development of anti-infective agents.
