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Pathogens 2016, 5(2), 44; doi:10.3390/pathogens5020044

Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets

Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, Sesto Fiorentino, Florence 50019, Italy
Academic Editor: Lawrence S. Young
Received: 14 May 2016 / Revised: 11 June 2016 / Accepted: 12 June 2016 / Published: 16 June 2016
(This article belongs to the Special Issue Pathogen Legionella pneumophila)
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Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4–8.3) × 105 s−1 and kcat/KM values of (4.7–8.5) × 107 M−1·s−1. In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. 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). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets. View Full-Text
Keywords: Legionella pneumophila; carbonic anhydrase; bacteria; inhibitor; antibiotic; virulence factor; sulfonamide Legionella pneumophila; carbonic anhydrase; bacteria; inhibitor; antibiotic; virulence factor; sulfonamide
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Supuran, C.T. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets. Pathogens 2016, 5, 44.

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