Pseudomonas aeruginosa β-carbonic anhydrase, psCA1, is required for calcium deposition and contributes to virulence

Lotlikar, Shalaka R.; Kayastha, Biraj B.; Vullo, Daniela; Khanam, Sharmily; Braga, Reygan E.; Murray, Akilah B.; McKenna, Robert; Supuran, Claudiu T.; Patrauchan, Marianna A.

doi:10.1016/j.ceca.2019.102080

Cited by 32 publications

(16 citation statements)

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“…Thus, CAs encoded in the genome of Helicobacter pylori, are essential for the acid acclimatisation of the pathogen within the stomach [13][14][15] ; Vibrio cholerae uses CAs as a system to colonise the host since CAs are involved in the production of sodium bicarbonate, which induces cholera toxin expression 16 ; Brucella suis needed functional CAs for growing [17][18][19][20] ; b-CA from Salmonella enterica is highly expressed during the bacterial infection 21 . Finally, the deletion of the gene encoding for the b-CA in Pseudomonas aeruginosa (psCA1) impaired virulence of the pathogen by reducing calcium salt depositions 22 . Starting from 1920, when was observed for the first time the CA activity in hemolyzed blood 23 , the knowledge of the enzymes responsible for that activity, i.e., the CA, has extensively been improved.…”

Section: Introductionmentioning

confidence: 99%

Bacterial ι-carbonic anhydrase: a new active class of carbonic anhydrase identified in the genome of the Gram-negative bacterium Burkholderia territorii

Prete

Nocentini

Capasso

2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The carbonic anhydrases (CAs, EC 4.2.1.1) catalyse a simple but physiologically crucial reversible reaction, the carbon dioxide hydration with the production of bicarbonate and protons. In the last years, and especially, to the rapid emergence of the bacterial antibiotic resistance that is occurring worldwide, the understanding of the function of bacterial CAs has increased significantly. Recently, a new CA-class (i-CA) was discovered in the marine diatom T. pseudonana. It has been reported that bacterial genomes may contain genes with relevant homology to the diatom i-class CA. Still, the catalytic activity of the enzyme encoded by the gene was not investigated. Thus, herein, for the first time, we cloned, expressed, and purified the recombinant bacterial i-CA (acronym BteCAi) identified in the genome of Burkholderia territorii. The recombinant BteCAi resulted in a good catalyst for the hydration of CO 2 to bicarbonate and protons, with a k cat of 3.0 Â 10 5 s À1 and k cat /K M of 3.9 Â 10 7 M À1 s À1 , and is also sensitive to inhibition by the sulphonamide acetazolamide. Furthermore, with the aid of the protonography, it has been demonstrated that BteCAi can be present as a dimer. This result is corroborated by the construction of a molecular model of BteCAi, which showed that the enzyme is formed by two equivalent monomers having a structure similar to a butterfly.

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Section: Introductionmentioning

confidence: 99%

Bacterial ι-carbonic anhydrase: a new active class of carbonic anhydrase identified in the genome of the Gram-negative bacterium Burkholderia territorii

Prete

Nocentini

Capasso

2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Many CA inhibitors (CAIs) exist and efficiently inhibit, in vitro, the activity of the CAs encoded by the genome of several pathogens [13,[16][17][18]. It has been demonstrated that CAIs are also effective in vivo, impairing the growth and virulence of several pathogens responsible of human diseases, such as Helicobacter pylori [19][20][21], Vibrio cholerae [22], Brucella suis [23][24][25][26], Salmonella enterica [27], and Pseudomonas aeruginosa [28]. Considering the three major criteria typifying the drug-target approach, it is evident that CAs meet the criteria (b) and (c) entirely.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Substituted Benzene-Sulfonamides and Clinically Licensed Drugs on the Catalytic Activity of CynT2, a Carbonic Anhydrase Crucial for Escherichia coli Life Cycle

Prete

Luca

Bua

et al. 2020

IJMS

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Proteins are relevant antimicrobial drug targets, and among them, enzymes represent a significant group, since most of them catalyze reactions essential for supporting the central metabolism, or are necessary for the pathogen vitality. Genomic exploration of pathogenic and non-pathogenic microorganisms has revealed genes encoding for a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the physiologically crucial reversible reaction of the carbon dioxide hydration to bicarbonate and protons. Herein, we investigated the sulfonamide inhibition profile of the recombinant β-CA (CynT2) identified in the genome of the Gram-negative bacterium Escherichia coli. This biocatalyst is indispensable for the growth of the microbe at atmospheric pCO2. Surprisingly, this enzyme has not been investigated for its inhibition with any class of CA inhibitors. Here, we show that CynT2 was strongly inhibited by some substituted benzene-sulfonamides and the clinically used inhibitor sulpiride (KIs in the range of 82–97 nM). This study may be relevant for identifying novel CA inhibitors, as well as for another essential part of the drug discovery pipeline, such as the structure–activity relationship for this class of enzyme inhibitors.

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“…Analogously, the genome of S. enterica serovar Typhimurium, a Gram-negative bacterium causing gastroenteritis ( Rollenhagen and Bumann, 2006 ), also encodes for a β-CA ( Nishimori et al, 2011 ; Vullo et al, 2011 ) that is highly expressed during the bacterial infection, as demonstrated by in vivo gene expression studies ( Rollenhagen and Bumann, 2006 ). In P. aeruginosa (psCA1), a Gram-negative bacterium commonly found in the environment, the β-CA gene’s deletion provoked a reduction of calcium salt depositions, impairing the microbe virulence ( Lotlikar et al, 2019 ). Finally, it was demonstrated that various CAs encoded by the H. pylori genome are essential for the acid tolerance/adaptation of the microbe in the stomach, a harsh environment with pH values as low as 1–2 ( Buzas, 2010 ; Modak et al, 2019 ).…”

Section: Bacterial Carbonic Anhydrases As Druggable Targetsmentioning

confidence: 99%

Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori

et al. 2021

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Our understanding of the function of bacterial carbonic anhydrases (CAs, EC 4.2.1.1) has increased significantly in the last years. CAs are metalloenzymes able to modulate CO2, HCO3– and H+ concentration through their crucial role in catalysis of reversible CO2 hydration (CO2 + H2O ⇄ HCO3– + H+). In all living organisms, CA activity is linked to physiological processes, such as those related to the transport and supply of CO2 or HCO3–, pH homeostasis, secretion of electrolytes, biosynthetic processes and photosynthesis. These important processes cannot be ensured by the very low rate of the non-catalyzed reaction of CO2 hydration. It has been recently shown that CAs are important biomolecules for many bacteria involved in human infections, such as Vibrio cholerae, Brucella suis, Salmonella enterica, Pseudomonas aeruginosa, and Helicobacter pylori. In these species, CA activity promotes microorganism growth and adaptation in the host, or modulates bacterial toxin production and virulence. In this review, recent literature in this research field and some of the above-mentioned issues are discussed, namely: (i) the implication of CAs from bacterial pathogens in determining the microorganism growth and virulence; (ii) the druggability of these enzymes using classical CA inhibitors (CAIs) of the sulfonamide-type as examples; (iii) the role played by Helicobacter pylori CAs in the acid tolerance/adaptation of the microbe within the human abdomen; (iv) the role of CAs played in the outer membrane vesicles spawned by H. pylori in its planktonic and biofilm phenotypes; (v) the possibility of using H. pylori CAIs in combination with probiotic strains as a novel anti-ulcer treatment approach. The latter approach may represent an innovative and successful strategy to fight gastric infections in the era of increasing resistance of pathogenic bacteria to classical antibiotics.

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Pseudomonas aeruginosa β-carbonic anhydrase, psCA1, is required for calcium deposition and contributes to virulence

Cited by 32 publications

References 105 publications

Bacterial ι-carbonic anhydrase: a new active class of carbonic anhydrase identified in the genome of the Gram-negative bacterium Burkholderia territorii

Bacterial ι-carbonic anhydrase: a new active class of carbonic anhydrase identified in the genome of the Gram-negative bacterium Burkholderia territorii

The Effect of Substituted Benzene-Sulfonamides and Clinically Licensed Drugs on the Catalytic Activity of CynT2, a Carbonic Anhydrase Crucial for Escherichia coli Life Cycle

Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori

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