Chemistry & Biochemistry
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Item Small Molecule Inhibitors of AI-2 Signaling in Bacteria: State-of-the-Art and Future Perspectives for Anti-Quorum Sensing Agents(MDPI, 2013-08-29) Guo, Min; Gamby, Sonja; Zheng, Yue; Sintim, Herman O.Bacteria respond to different small molecules that are produced by other neighboring bacteria. These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species). AI-2 has been proposed as an interspecies autoinducer and has been shown to regulate different bacterial physiology as well as affect virulence factor production and biofilm formation in some bacteria, including bacteria of clinical relevance. Several groups have embarked on the development of small molecules that could be used to perturb AI-2 signaling in bacteria, with the ultimate goal that these molecules could be used to inhibit bacterial virulence and biofilm formation. Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors. In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules.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.