| Quorum sensing (QS) is a mechanism of communication used by bacteria to coordinate gene expression via the exchange of diffusible chemical signals, called autoinducers. The synchronization of gene expression allows bacterial populations to engage in behaviors that are beneficial to groups of bacteria rather than individual cells, and include regulation of bioluminescence, formation of biofilms, and secretion of virulence factors. Illustrated in the latter two examples are the dire consequences on human health exerted by a coordinated group of bacteria, and as a result, QS has become an area of intense research both to understand the molecular mechanisms of this process and to mitigate the deleterious effects of a unified bacterial population. This thesis describes efforts to modulate QS through the design and synthesis of analogs of natural autoinducers, as well as the antibacterial activity of an autoinducer-derived natural product.;The thesis concludes with Chapter 5, which is a departure from the development of AI-2 modulators into the description of the antibacterial activity of a natural product formed from an autoinducer of the human pathogen Pseudomonas aeruginosa. In this context, it is possible to envision a scenario in which QS not only plays a role in the coordination of bacterial behavior and function, but also in the interspecies warfare that occurs in environmental settings.;The thesis begins with an overview of the development of autoinducer analogs, with a focus on the methodologies used and the structural relationships between the agonists or antagonists discovered and the natural signals. Chapter 2 details work towards the modulation of QS in the bioluminescent marine bacterium Vibrio harveyi. These studies were directed at finding agonists or antagonists of AI-2-based QS, a proposed interspecies signaling system, and several agonists were uncovered. Building on these findings, Chapter 3 describes the discovery of potent antagonists of the AI-2 QS of the human pathogen Salmonella typhimurium. The activity of these analogs is further elaborated in Chapter 4, where they are compared directly to the current "gold standard" of AI-2 QS inhibition and were found to be more potent antagonists of QS and less toxic towards mammalian cells. |
