Document Type

Dissertation

Abstract

In recent years the frequency of antibiotic resistance has been on the rise creating a need for antibiotic development with specific and lethal targets. It has been recently reported that glycosyl trizole are a novel class of antibacterial agents (1). Further investigation on the antibacterial ability of glycosyl triazole inhibitors has shown that targets include exo-acting N-acetylglucosaminidases (GlcNAcase) LytG (Bacillus subtilis) and FlgJ (Salmonella enterica) of the GH73 family (2). The Glycoside Hydrolase Family 73 (GH73) is characterized by bacterial and viral glycoside hydrolase. This enzyme cleaves the β-1,4-glycosidic linkage between N-acetylglucosaminyl (NAG) and N-acetylmuramyl (NAM) of the carbohydrate backbone in bacterial peptidoglycan. Glycoside hydrolase can occur as an endo- or exo- process, depending on the region of the chain that is cleaved. Endo-acting refers to activity in the middle of the chain, whereas exo-acting refers to the ends (typically the non-reducing end) (3). Currently, there is no kinetic parameters that have been determined for any member of the GH73 family, however binding and kinetic characterization will be performed for select glycosyl triazole inhibitors and GH73 targets interactions. Further studies will involve crystallization and GlcNAcase activity assays to identify GH73 family members as the target of glycosyl triazole inhibitors. Through these studies the interaction between the non-competing inhibitor and the GH73 target will be characterized. Additionally, it will be demonstrated that these Ugi- derived compounds are competitive inhibitors of GH73 enzymes.

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