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Bioorg Med Chem. 2014 Jun 1;22(11):2939-46. doi: 10.1016/j.bmc.2014.04.006. Epub 2014 Apr 13.

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

Author information

1
Department of Gastroenterology, Kochi Medical School, Kochi, Japan.
2
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
3
Istituto di Biochimica delle Proteine-CNR, Via P. Castellino 111, 80131 Napoli, Italy.
4
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, Polo Scientifico, Dipartimento di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

Abstract

Two β-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 kcat in the range of (3.4-8.3) × 10(5)s(-1) and kcat/Km of (4.7-8.5) × 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(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). 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.

KEYWORDS:

Antibacterial agent; Carbonic anhydrase; Legionella pneumophila; Sulfonamide

PMID:
24792813
DOI:
10.1016/j.bmc.2014.04.006
[Indexed for MEDLINE]

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