Brucella Carbonic Anhydrases: New Targets for Designing Anti-Infective Agents

Jean-Yves      Winum; Stephan      Kohler; Claudiu      T. Supuran

Abstract

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 CO2 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 were 13 clinically tested drugs, was used for inhibition studies with bsCA I and II. These compounds were generally much more potent inhibitors of bsCA I (KIs of 17-75 nM) than of bsCA II (KIs of 84-923nM). However, certain glycosidic sulfonamide derivatives exhibited the same strong inhibitory activity on both bsCA I and bsCA II (KIs 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.

Keywords: β-carbonic anhydrase, Brucella suis, inhibition, brucellosis, sulfonamide, zoonotic agent, carbonic anhydrases, metalloproteins, acetazolamide, sulfonamide drug, glycosidic sulfonamide, glycosylsulfonamides, cocco-bacilli, dendritic cells, Helicobacter pylori, Mycobacterium tuberculosis, bsCA I, sulfamate, methazolamide, ethoxzolamide, dichorophenamide, dorzolamide, brinzolamide, benzolamide, topiramate, zonisamide, sulpiride, indisulam, celecoxib, valdecoxib, glycosylsulfonamide