Abstract

Antibiotic resistance has become a global health threat, and with more bacteria becoming resistant to antibiotic drugs, novel strategies to fight infection are needed. Antivirulence as a strategy differs from others as it focuses on blocking virulence factors instead of directly killing the bacteria. One prominent virulence factor is biofilm formation, which initially occurs when bacteria adhere to the surface of a host cell through lectin-carbohydrate binding. Anti-adhesion strategies aim to stop this binding with synthetic sugars that have higher selectivity for the lectins than the natural ligands. In this research, derivatives of N-acetylglucosamine (GlcNAc) are synthesized as inhibitors to block the F17G and GafD lectins on Escherichia coli (E. coli) bacteria, therefore preventing the adhesion step of biofilm formation. The amide at C2 of GlcNAc is the target of derivation, and this amide group has been manipulated by changing factors like the length of the carbon chain, sterics, and electronics. To synthesize these derivatives, the amine of glucosamine hydrochloride was protected as an imine, and the hydroxyl groups were acetylated. The amine was selectively deprotected to provide a free amine for derivation. From this amine, hexanoyl, butyryl, and benzoyl amides have been synthesized. Deacetylation of the amide derivatives by first making an O-methyl glycoside has been optimized to restore the hydroxyl groups on the sugar. Once a small library of GlcNAc amide derivatives has been completed, the potential inhibitors will be tested for binding to GafD in an ELISA-like assay, which will contribute to further knowledge of the effectiveness of anti-adhesion strategies against E. coli infection.

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