Structural determinant for Helicobacter pylori resistance to sulfonamides

Bacterial dihydropterorate synthase (DHPS) is a key enzyme in the folic acid biosynthesis. In many pathogens, DHPS is the molecular target of sulfa drugs (sulfonamides). Sulfonamides act as competitive inhibitors by occupying the binding pocket for the substrate p-aminobenzoic acid. Despite the high degree of crossspecies sequence conservation in the p-aminobenzoic-acid-binding site, some bacteria are not sensitive to these drugs. This work addresses the molecular mechanism of resistance of Helicobacter pylori DHPS to sulfonamides. Homology modelling, structural and sequence analysis identify a single amino acid substitution in the substrate-binding pocket as the major determinant for its resistance. Structure-guided rational modification of sulfonamides to fit the specific architecture of the H. pylori enzyme s active site may be a strategy to develop novel antimicrobial agents with specific activity against H. pylori.