Silencing bacteria with small molecules

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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.