1. Sulfonamide inhibition profile of the γ-carbonic anhydrase identified in the genome of the pathogenic bacterium Burkholderia pseudomallei the etiological agent responsible of melioidosis.
- Author
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Del Prete S, Vullo D, Di Fonzo P, Osman SM, AlOthman Z, Donald WA, Supuran CT, and Capasso C
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Burkholderia pseudomallei enzymology, Carbonic Anhydrase Inhibitors chemical synthesis, Carbonic Anhydrase Inhibitors chemistry, Dose-Response Relationship, Drug, Humans, Melioidosis metabolism, Melioidosis microbiology, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Anti-Bacterial Agents pharmacology, Burkholderia pseudomallei drug effects, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases metabolism, Melioidosis drug therapy, Sulfonamides pharmacology
- Abstract
A new γ-carbonic anhydrase (CA, EC 4.1.1.1) was cloned and characterized kinetically in the genome of the bacterial pathogen Burkholderia pseudomallei, the etiological agent of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. The catalytic activity of this new enzyme, BpsCAγ, is significant with a k
cat of 5.3×105 s-1 and kcat /Km of 2.5×107 M-1 ×s-1 for the physiologic CO2 hydration reaction. The inhibition constant value for this enzyme for 39 sulfonamide inhibitors was obtained. Acetazolamide, benzolamide and metanilamide were the most effective (KI s of 149-653nM) inhibitors of BpsCAγ activity, whereas other sulfonamides/sulfamates such as ethoxzolamide, topiramate, sulpiride, indisulam, sulthiame and saccharin were active in the micromolar range (KI s of 1.27-9.56μM). As Burkholderia pseudomallei is resistant to many classical antibiotics, identifying compounds that interfere with crucial enzymes in the B. pseudomallei life cycle may lead to antibiotics with novel mechanisms of action., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2017
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