Structure Activity Relationship for Sulfonamide Inhibition of Helicobacter pylori α-Carbonic Anhydrase

alpha-Carbonic anhydrase of Helicobacter pylori (Hp alpha CA) plays an important role in the acclimation of this oncobacterium to the acidic pH of the stomach. Sulfonamide inhibitors of Hp alpha CA possess anti-H. pylon activity. The crystal structures of complexes of Hp alpha CA with a family of acetazolamide-related sulfonamides have been determined. Analysis of the structures revealed that the mode of sulfonamide binding correlates well with their inhibitory activities. In addition, comparisons with the corresponding inhibitor complexes of human carbonic anhydrase II (HCAII) indicated that Hp alpha CA possesses an additional, alternative binding site for sulfonamides that is not present in HCAII. Furthermore, the hydrophobic pocket in HCAII that stabilizes the apolar moiety of sulfonamide inhibitors is replaced with a more open, hydrophilic pocket in Hp alpha CA. Thus, our analysis identified major structural features can be exploited in the design of selective and more potent inhibitors of Hp alpha CA that may lead to novel antimicrobials.