Inhibition of glycoprotein biosynthesis in the pathogenic bacterium Helicobacter pylori by masked carbohydrate phosphonates

Abstract

The glycan-rich surface of Helicobacter pylori plays a critical role in host–pathogen interactions and represents a promising target for therapeutic intervention. We report the synthesis and biological evaluation of a masked bis(pivaloyloxymethyl) phosphonate analogue of α-D-glucose 1-phosphate designed to inhibit glycoprotein biosynthesis in H. pylori. This prodrug strategy enhances bacterial uptake by neutralizing the phosphonate's dianionic charge, potentially enabling intracellular esterase-mediated release of the active phosphonate. Using metabolic oligosaccharide engineering (MOE) with Ac₄GlcNAz, we demonstrate that the masked phosphonate exhibits dose-dependent inhibition of glycoprotein biosynthesis, whereas unmasked and cyclic phosphonate analogues show minimal activity. These findings highlight the potential of masked phosphonates as chemical tools for probing bacterial glycosylation and as leads for novel antibacterial agents.