Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2, Bâtiment de Recherche Max Mousseron, EcoleNationale Supérieure de Chimie de Montpellier, 8 rue de l’Ecole Normale, Montpellier Cedex, France.
Curr Pharm Des. 2010;16(29):3310-6. doi: 10.2174/138161210793429850.
The facultative intracellular pathogen and zoonotic agent Brucella sp. possesses two carbonic anhydrases (CAs, EC 4.2.1.1), termed bsCA I and bsCA II (in Brucella suis), belonging to the β-class of these metalloproteins. These zinc enzymes, present in many other pathogenic bacteria, have been considered recently as potential antibacterial targets. The catalytic activity of bsCA II is higher than that of bsCA I (for the conversion of CO(2) to bicarbonate). Both enzymes were inhibited by the well-studied inhibitor acetazolamide, a sulfonamide drug. A library of 41 sulfonamides and one sulfamate, among which 12 clinically tested drugs, was used for inhibition studies with bsCA I and II. These compounds were generally much more potent inhibitors of bsCA I (K(Is) of 17-75 nM) than of bsCAII (K(I)s of 84-923nM). However, certain glycosidic sulfonamide derivatives exhibited the same strong inhibitory activity on both bsCA I and bsCA II (K(Is) of 8.9-20 nM). Furthermore, at least one of these glycosylsulfonamides showed a significant inhibition of B. suis growth after 8-11 days of culture in minimal medium. In conclusion, as β-CAs of Brucella are susceptible to inhibition by a wide range of aromatic and heteroaromatic sulfonamides, they may represent novel targets for the development of clinically useful antibacterial agents.
兼性细胞内病原体和人畜共患病原菌布鲁氏菌属（Brucella sp.）拥有两种碳酸酐酶（CA，EC 4.2.1.1），分别称为 bsCA I 和 bsCA II（在猪布鲁氏菌中），属于这些金属蛋白酶的β类。这些锌酶存在于许多其他致病性细菌中，最近被认为是潜在的抗菌靶标。bsCA II 的催化活性高于 bsCA I（用于将 CO(2)转化为碳酸氢盐）。两种酶都被研究充分的抑制剂乙酰唑胺（磺胺类药物）抑制。使用了一个由 41 种磺胺类药物和一种磺胺酸盐组成的文库，其中包括 12 种临床测试药物，用于 bsCA I 和 II 的抑制研究。这些化合物通常对 bsCA I 的抑制作用更强（K(Is)为 17-75 nM），而对 bsCAII 的抑制作用较弱（K(I)s 为 84-923 nM）。然而，某些糖基磺胺衍生物对 bsCA I 和 bsCA II 具有相同的强抑制活性（K(Is)为 8.9-20 nM）。此外，这些糖基磺胺类化合物中的至少一种在最小培养基中培养 8-11 天后对猪布鲁氏菌的生长表现出明显的抑制作用。总之，由于布鲁氏菌的β-CAs 易受广泛的芳香族和杂环磺酰胺的抑制，它们可能成为开发临床有用的抗菌药物的新靶标。
