Supuran Claudiu T
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, Sesto Fiorentino, Florence 50019, Italy.
Pathogens. 2016 Jun 16;5(2):44. doi: 10.3390/pathogens5020044.
Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO₂ hydration, with kcat values in the range of (3.4-8.3) × 10⁵ s(-1) and kcat/KM values of (4.7-8.5) × 10⁷ M(-1)·s(-1). In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3-90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2-88.5 nM). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets.
碳酸酐酶（CAs，EC 4.2.1.1）是一类金属酶，可催化二氧化碳水合形成碳酸氢根和质子。许多致病细菌都编码属于α-、β-和/或γ-CA家族的此类酶。在过去十年中，包括嗜肺军团菌在内的一些病原体中的酶已被克隆并详细表征。这些酶被证明是高效的二氧化碳水合催化剂，催化常数（kcat）值在（3.4 - 8.3）× 10⁵ s⁻¹范围内，催化常数与米氏常数的比值（kcat/KM）值为（4.7 - 8.5）× 10⁷ M⁻¹·s⁻¹。针对该病原体的两种β-CA（LpCA1和LpCA2），也报道了用各类抑制剂进行的体外抑制研究，如阴离子、磺胺类和氨基磺酸盐类。无机阴离子是毫摩尔级抑制剂，而二乙基二硫代氨基甲酸盐、氨基磺酸盐、磺胺、苯硼酸和苯胂酸是微摩尔级抑制剂。LpCA1的最佳抑制剂是氨基苯甲酰胺和结构相似的磺酰化芳族磺胺，以及乙酰唑胺和乙氧唑胺（抑制常数KIs在40.3 - 90.5 nM范围内）。LpCA2的最佳抑制剂属于同一类磺酰化磺胺，还有乙酰唑胺、甲醋唑胺和二氯苯酰胺（抑制常数KIs在25.2 - 88.5 nM范围内）。考虑到这些初步结果，该病原体的两种细菌碳酸酐酶是有前景但尚未充分探索的靶点，有望获得不存在大多数临床使用抗生素常见耐药问题的抗菌药物，但需要进一步研究以在体内验证它们作为药物靶点的有效性。
