Bacterial communication and its role as a target for nanoparticlebased antimicrobial therapy.

摘要

The goal of this dissertation is to establish the environmental and public health importance of alternative forms of antimicrobial therapy, specifically those that utilize nanotechnology to combat quorum sensing-controlled bacterial infections. Quorum sensing (i.e. chemical communication) is an inherent characteristic that is essential to bacterial pathogenesis and biofilm formation (where most infections occur). A thorough review of the literature has been conducted to establish an understanding of the state of nanotechnology research as it relates to combatting bacterial infections. This synthesis, provided in Chapter 1, demonstrates how the chemical and structural designs of nanoparticles can be manipulated to specifically target bacterial infections.;Next, an investigation into the development and novel use of nanoparticles engineered to shut down bacterial quorum sensing is given in Chapter 2. Inhibiting the quorum sensing process is significant because it does not kill the bacteria, and therefore does not exacerbate antibiotic resistance. Briefly, the model system demonstrates that beta-cyclodextrin functionalized nanoparticles are able to persist in the bacterial cell environment and quench extracellular bacterial communication molecules, and effectively silence bacterial communication. The system neutralizes communication through chelation of common signaling molecules called acyl-homoserine lactones. The new technology described here provides a seminal step in developing anti-virulence therapies that will not contribute to antibiotic resistance, and do not rely on traditional antimicrobials. Also, this technology utilizes non-toxic nanoparticles that can be functionalized with biologically-active compounds and tailored to meet specific needs. This study provides a scaffold and critical stepping stone that will promote more-tailored future developments in nanoparticle-based antimicrobial therapy.;Chapter 3 provides insight into the environmental importance of bacterial communication, and the steps taken by bacteria to protect the valuable signal molecules. Briefly, environmental biofilms consist of extrapolymeric substances with a high concentration of nonreducing sugars, such as trehalose. Previous studies have shown that trehalose is commonly utilized by soil bacteria during periods of drought to maintain membrane stability and preserve the structure of proteins. The study presented in Chapter 3 demonstrates that trehalose plays a role in protecting quorum sensing signals during desiccation through the formation of an extracellular glass. Additionally, the study provides a survey of the complexity of microbial ecosystems and the role that biofilm components play in the natural environment. Together, the three chapters of this dissertation demonstrate the importance of quorum sensing to bacteria and as a target for nanoparticle-based antimicrobial therapy.