Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets
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 Legionel...
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| Format: | Article |
| Language: | English |
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MDPI AG
2016-06-01
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| Series: | Pathogens |
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| Online Access: | http://www.mdpi.com/2076-0817/5/2/44 |
| _version_ | 1798002748124299264 |
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| author | Claudiu T. Supuran |
| author_facet | Claudiu T. Supuran |
| author_sort | Claudiu T. Supuran |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T11:57:05Z |
| format | Article |
| id | doaj.art-19e0f8f699804f7081f2407755db05c9 |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-04-11T11:57:05Z |
| publishDate | 2016-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-19e0f8f699804f7081f2407755db05c92022-12-22T04:25:05ZengMDPI AGPathogens2076-08172016-06-01524410.3390/pathogens5020044pathogens5020044Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug TargetsClaudiu T. Supuran0Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, Sesto Fiorentino, Florence 50019, ItalyCarbonic 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.http://www.mdpi.com/2076-0817/5/2/44Legionella pneumophilacarbonic anhydrasebacteriainhibitorantibioticvirulence factorsulfonamide |
| spellingShingle | Claudiu T. Supuran Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets Pathogens Legionella pneumophila carbonic anhydrase bacteria inhibitor antibiotic virulence factor sulfonamide |
| title | Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets |
| title_full | Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets |
| title_fullStr | Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets |
| title_full_unstemmed | Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets |
| title_short | Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets |
| title_sort | legionella pneumophila carbonic anhydrases underexplored antibacterial drug targets |
| topic | Legionella pneumophila carbonic anhydrase bacteria inhibitor antibiotic virulence factor sulfonamide |
| url | http://www.mdpi.com/2076-0817/5/2/44 |
| work_keys_str_mv | AT claudiutsupuran legionellapneumophilacarbonicanhydrasesunderexploredantibacterialdrugtargets |