Theses and Dissertations from UMD
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Item Dual Quorum Quenching Capsules: Disrupting two bacterial communication pathways that lead to virulence(2016) Rhoads, Melissa Katherine; Bentley, William E; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Healthcare Associated Infections (HAIs) in the United States, are estimated to cost nearly $10 billion annually. And, while device-related infections have decreased, the 60% attributed to pneumonia, gastrointestinal pathogens and surgical site infections (SSIs) remain prevalent. Furthermore, these are often complicated by antibacterial resistance that ultimately cause 2 million illnesses and 23,000 deaths in the US annually. Antibacterial resistance is an issue increasing in severity as existing antibiotics are losing effectiveness, and fewer new antibiotics are being developed. As a result, new methods of combating bacterial virulence are required. Modulating communications of bacteria can alter phenotype, such as biofilm formation and toxin production. Disrupting these communications provides a means of controlling virulence without directly interacting with the bacteria of interest, a strategy contrary to traditional antibiotics. Inter- and intra-species bacterial communication is commonly called quorum sensing because the communication molecules have been linked to phenotypic changes based on bacterial population dynamics. By disrupting the communication, a method called ‘quorum quenching’, bacterial phenotype can be altered. Virulence of bacteria is both population and species dependent; each species will secrete different toxic molecules, and total population will affect bacterial phenotype9. Here, the kinase LsrK and lactonase SsoPox were combined to simultaneously disrupt two different communication pathways with direct ties to virulence leading to SSIs, gastrointestinal infection and pneumonia. To deliver these enzymes for site-specific virulence prevention, two naturally occurring polymers were used, chitosan and alginate. Chitosan, from crustacean shells, and alginate, from seaweed, are frequently studied due to their biocompatibility, availability, self-assembly and biodegrading properties and have already been verified in vivo for wound-dressing. In this work, a novel functionalized capsule of quorum quenching enzymes and biocompatible polymers was constructed and demonstrated to have dual-quenching capability. This combination of immobilized enzymes has the potential for preventing biofilm formation and reducing bacterial toxicity in a wide variety of medical and non-medical applications.Item Silencing bacteria with small molecules(2014) Guo, Min; Sintim, Herman O; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Quorum sensing (QS) is a phenomenon in bacteria where the accumulation of extracellular signaling molecules (autoinducers, AIs), which enable bacterial cells to sense neighboring cells (population density), reaches certain threshold and triggers group behaviors of bacteria including virulence production and biofilm formation. The inhibition of QS and hence toxin production or biofilm formation by pathogenic bacteria has been suggested as an alternative strategy to deal with the problem of bacterial resistance to traditional antibiotics. Inhibiting QS will not kill bacteria, however the expectation is that resistance to a QS antagonist will not be as widespread as it is for traditional cytotoxic antibiotics. In Chapters 2 and 3 of this dissertation, we report the syntheses and biological evaluations of various analogs (C1 substituted, ester protected and 3,3-dihalogenated) of a universal QS signaling molecule, AI-2, which is found in both Gram-positive and Gram-negative bacteria. We report that modifications to the native AI-2 molecule affords analogs that can potently inhibit QS processes in E. coli and Salmonella. In Chapter 4, we explore the development of small molecule modulators of species-specific acylhomoserine lactone autoinducers, called AI-1. In the past three decades, intensive efforts have been dedicated to the development of modulators of AI-1-based QS signaling. The majority of modulators, reported to date, have kept the lactone head group and modified the acyl tail. These synthetic modulators, although effective, are not drug-like because lactones are susceptible to chemical and enzymatic hydrolysis. We demonstrate that 3-aminooxazolidinone based AI-1 analogs, which are hydrolytically more stable than homoserine lactone-based compounds, can also modulate AI-1-based QS.