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Title: Manipulating Quorum Sensing to Control Bacterial Pathogenicity
Authors: O'Loughlin, Colleen Tara
Advisors: Bassler, Bonnie L.
Contributors: Molecular Biology Department
Keywords: Biofilm
P. aeruginosa
Quorum Sensing
Small molecule
Subjects: Molecular biology
Issue Date: 2014
Publisher: Princeton, NJ : Princeton University
Abstract: Quorum sensing is a process of communication used by bacteria to monitor changes in population density and alter behavior in response to these changes. This process is dependent on the production, release, and detection of signaling molecules called autoinducers. When few bacteria are present, autoinducers exist in the local environment at low concentrations. As the density of cells increases, autoinducer concentration does as well. At a critical concentration of autoinducer, cognate receptors detect autoinducers and relay this information, resulting in alteration of gene expression, and consequently, bacterial behaviors. Pathogenic bacteria frequently use quorum sensing as a way to control the timing and expression of virulence factors and biofilms. Of particular interest to this work are two opportunistic human pathogens Chromobacterium violaceum and Pseudomonas aeruginosa. Both P. aeruginosa and C. violaceum use acyl-homoserine lactone autoinducers to monitor population density and control expression of virulence factors. Both species use cytoplasmic LuxR-type receptors that not only detect their cognate homoserine lactones, but also function as transcription factors to control expression of virulence factors, biofilm formation, and other determinants of pathogenicity. The experiments described in this thesis reveal that small molecules that are structurally similar to native homoserine lactones are able to potently inhibit the LuxR receptors in both C. violaceum and P. aeruginosa. These modulators of quorum sensing compete for the ligand-binding pocket of the receptors and induce conformations in the LuxR proteins that reduce, or eliminate, their ability to bind target genes, recruit RNA polymerase, and activate gene expression. As such, these molecules reduce production of crucial virulence factors. The reduction of virulence factors results in enhanced survival of Caenorhabditis elegans upon infection with C. violaceum or P. aeruginosa. Additional work demonstrates that treatment of P. aeruginosa attenuates the quorum-sensing mediated killing of human lung epithelial cells.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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