Sulfonamide inhibition studies of two beta-carbonic anhydrases from the bacterial pathogen Legionella pneumophila

Two beta-carbonic anhydrases (CAs, EC 4.2.1.1) were identified, cloned and purified in the pathogenic bacterium Legionella pneumophila, denominated LpCA1 and LpCA2. They efficiently catalyze CO2 hydration to bicarbonate and protons, with k(cat) in the range of (3.4-8.3) x 10(5) s(-1) and k(cat)/ K-m of (4.7-8.5) x 10(7) M-1 s(-1), and are inhibited by sulfonamides and sulfamates. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide(K(I)s 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 (K(I)s in the range of 25.2-88.5 nM). As these enzymes may be involved in pH regulation in the phagosome during Legionella infection, their inhibition may lead to antibacterials with a novel mechanism of action. (C) 2014 Elsevier Ltd. All rights reserved.