Brucella carbonic anhydrases: new targets for designing anti-infective agents.
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 &beta;-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 &beta;-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.
Winum
Jean-Yves
JY
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. jean-yves.winum@univ-montp2.fr
Köhler
Stephan
S
Supuran
Claudiu T
CT
D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D002002:Brucella / Q000187:drug effects / Q000201:enzymology*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000187:drug effects*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology
D000890:Anti-Infective Agents; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; D002256:Carbonic Anhydrases