Sulfonamide inhibition profile of the γ-carbonic anhydrase identified in the genome of the pathogenic bacterium Burkholderia pseudomallei the etiological agent responsible of melioidosis

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• 作者：Sonia Del Prete^a ; Daniela Vullo^b ; Pietro Di Fonzo^a ; Sameh M. Osman^c ; Zeid AlOthman^c ; William A. Donald^d ; Claudiu T. Supuran^c ; ^d ; ^e ; ^{claudiu.supuran@unifi.it} ; Clemente Capasso^a ; ^{clemente.capasso@ibbr.cnr.it}
• 关键词：Carbonic anhydrase ; γ-Class ; Inhibitor ; Sulfonamide ; Sulfamate ; Acetazolamide ; Drug resistance ; Burkholderia pseudomallei
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：490-495
• 全文大小：556 K
• 卷排序：27

文摘

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 kcat 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 (KIs of 149–653 nM) inhibitors of BpsCAγ activity, whereas other sulfonamides/sulfamates such as ethoxzolamide, topiramate, sulpiride, indisulam, sulthiame and saccharin were active in the micromolar range (KIs of 1.27–9.56 μM). 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.