4.6 Article

Anion inhibition studies of the α-carbonic anhydrases from Neisseria gonorrhoeae

Journal

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 36, Issue 1, Pages 1061-1066

Publisher

TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.1929202

Keywords

Carbonic anhydrase; inhibitor; anion; Neisseria gonorrhoeae; dithiocarbamate

Funding

  1. Italian Ministry for University and Research (MIUR) [FISR2019_04819 BacCAD]
  2. Purdue Institute for Drug Discovery Programmatic Grant
  3. NIH/NIAID [1R01AI148523]

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The study investigated the inhibition of Neisseria gonorrhoeae's alpha-class carbonic anhydrase NgCA by various inorganic and organic anions. The most effective inhibitors were found to be sulfamide, sulfamate, trithiocarbonate, and N,N-diethyldithiocarbamate, showcasing the potential for developing novel antibacterial drugs.
The bacterial pathogen Neisseria gonorrhoeae encodes for an alpha-class carbonic anhydrase (CA, EC 4.2.1.1), NgCA, which was investigated for its inhibition with a series of inorganic and organic anions. Perchlorate and hexafluorophosphate did not significantly inhibit NgCA CO2 hydrase activity, whereas the halides, azide, bicarbonate, carbonate, stannate, perosmate, diphosphate, divanadate, perruthenate, and trifluoromethanesulfonate showed inhibition constants in the range of 1.3-9.6 mM. Anions/small molecules such as cyanate, thiocyanate, nitrite, nitrate, bisulphite, sulphate, hydrogensulfide, phenylboronic acid, phenylarsonic acid, selenate, tellurate, tetraborate, perrhenate, peroxydisulfate, selenocyanate, iminodisulfonate, and fluorosulfonate showed K(I)s in the range of 0.15-1.0 mM. The most effective inhibitors detected in this study were sulfamide, sulfamate, trithiocarbonate and N,N-diethyldithiocarbamate, which had K(I)s in the range of 5.1-88 mu M. These last compounds incorporating the CS2 (-) zinc-binding group may be used as leads for developing even more effective NgCA inhibitors in addition to the aromatic/heterocyclic sulphonamides, as this enzyme was recently validated as an antibacterial drug target for obtaining novel antigonococcal agents

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