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

α-Carbonic
anhydrase of Helicobacter pylori (HpαCA)
plays an important role in the acclimation of this
oncobacterium to the acidic pH of the stomach. Sulfonamide inhibitors
of HpαCA possess anti-H. pylori activity. The crystal structures of complexes of HpαCA 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 HpαCA 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 HpαCA. Thus, our analysis identified major structural
features can be exploited in the design of selective and more potent
inhibitors of HpαCA that may lead to novel antimicrobials.