Abstract

Antibiotic resistance is a global health threat perpetuated by current antibiotic practices. Antivirulence is a novel method of combating bacterial infections that involves disarming the infection strategies of bacteria without killing them, thereby decreasing selective pressures leading to resistance. Biofilm formation is a virulence factor occurring in roughly sixty-five percent of all microbial infections. Upon adhesion to a host surface, bacteria colonize and begin to form an extracellular matrix that protects the bacteria from immune and drug defenses and makes infections much harder to treat. Anti-adhesion therapy is a method of antivirulence that uses synthetic sugars to prevent adhesion to host cells and thus inhibit biofilm formation. Rising resistance in the common bacteria Escherichia coli (E. coli) is of particular concern. E. coli lectins F17G and GafD bind N-acetyl-ß-D-glucosamine-presenting receptors on the microvilli of epithelial cells causing diarrheal illness, urinary tract infections, and other complications. Adhesion of enterotoxigenic E.coli to microvilli can be inhibited by incubation with N-acetylglucosamine, commonly known as GlcNAc. This study works to develop high affinity derivatives of GlcNAc to maximize inhibition of bacterial adhesion, and thereby prevent biofilm formation and reduce bacterial virulence. Inhibitors are synthesized through glycosidation of per-acetylated GlcNAc with various alcohols, followed by deacetylation to remove the protecting groups. Benzyl, hexyl, and phenyl glycosides are successfully developed. Flash column chromatography and nuclear magnetic resonance (NMR) are used for purification and structure determination, respectively. Computational studies with AutoDock Vina and Pymol are performed to assess docking of the GlcNAc derivatives in the receptor protein. The benzyl glycoside is found to have the highest binding affinity, followed by phenyl. The hexyl glycoside does not show a significant improvement to the binding affinity of the natural GlcNAc ligand. This work complements previous research on various E.coli lectins and offers novel insight into F17G binding of GlcNAc derivatives for adhesion inhibition.

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