Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 14, Issue 1, Pages 103-109Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00471
Keywords
Neisseria gonorrhoeae ?-carbonic anhydrase; carbonic anhydrase inhibitors; antibiotics; X-ray crystallography
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Drug-resistant Neisseria gonorrhoeae poses a serious threat to public health. The research team solved the structure of carbonic anhydrase inhibitors bound to the essential alpha-carbonic anhydrase isoform from N. gonorrhoeae, revealing differences compared to the human enzyme.
Drug-resistant Neisseria gonorrhoeae is a critical threat to public health, and bacterial carbonic anhydrases expressed by N. gonorrhoeae 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 N. gonorrhoeae, 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 alpha-carbonic anhydrase isoform from N. gonorrhoeae. The structural data for the analogs presented bound to N. gonorrhoeae alpha-carbonic anhydrase supports the observed structure-activity relationship for in vitro 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 N. gonorrhoeae alpha-carbonic anhydrase and the human carbonic anhydrase II isoform.
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