Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to <i>Neisseria gonorrhoeae</i> α-Carbonic Anhydrase.

Abstract

Drug-resistant <i>Neisseria gonorrhoeae</i> is a critical threat to public health, and bacterial carbonic anhydrases expressed by <i>N. gonorrhoeae</i> are potential new therapeutic targets to combat this pathogen. To further expand upon our recent reports of bacterial carbonic anhydrase inhibitors for the treatment of <i>N. gonorrhoeae</i>, our team has solved ligand-bound crystal structures of the FDA-approved carbonic anhydrase inhibitor acetazolamide, along with three analogs, in complex with the essential α-carbonic anhydrase isoform from <i>N. gonorrhoeae</i>. The structural data for the analogs presented bound to <i>N. gonorrhoeae</i> α-carbonic anhydrase supports the observed structure-activity relationship for <i>in vitro</i> inhibition with this scaffold against the enzyme. Moreover, the ligand-bound structures indicate differences in binding poses compared to those traditionally observed with the close human ortholog carbonic anhydrase II. These results present key differences in inhibitor binding between <i>N. gonorrhoeae</i> α-carbonic anhydrase and the human carbonic anhydrase II isoform.