Bacterial Carbonic Anhydrases as Drug Targets: Toward Novel Antibiotics?

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, the α-CAs from Neisseria spp. and Helicobacter pylori as well as the β-class enzymes from Escherichia coli, H. pylori, Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, and Haemophilus influenzae have been cloned and characterized in detail. For some of these enzymes the X-ray crystal structures were determined, and in vitro and in vivo inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates reported. Although efficient inhibitors have been reported for many such enzymes, only for Neisseria spp., H. pylori, B. suis, and S. pneumoniae enzymes it has been possible to evidence inhibition of bacterial growth in vivo. Thus, bacterial CAs represent promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets.

Biochemical properties of a novel and highly thermostable bacterial α-carbonic anhydrase fromSulfurihydrogenibium yellowstonense YO3AOP1

“…α-, β-and γ-CAs, with the β-class enzymes being the most diffuse 8 . Within the Bacteria domain, the enzymes purified from Neisseria gonorrhoeae, Neisseria sicca and Helicobacter pylori belong to the α class [9][10][11][12] .…”

“…Instead, the H. pylori CA displayed an activity similar to that of the human isoform hCA I for the CO 2 hydration reaction 11 . CAs belonging to the β-class were cloned, purified, and characterized from Escherichia coli, Salmonella enterica, Helicobacter pylori, Haemophilus influenza and from other pathogens 8 . The tri-dimensional structures of these enzymes are similar to that of the Salmonella enterica (stCA 1) 13 .…”

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

“…After this bacteriostatic agent, a range of analogs has entered into clinical use (constituting the so-called sulfa drug class of antibacterials), and many of these compounds are still widely used (Fig. 2) [44]. Derivative used clinically, among which acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide and brinzolamide, bind in a tetrahedral geometry to the Zn(II) ion in deprotonated state (Fig.…”

“…Derivative used clinically, among which acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide and brinzolamide, bind in a tetrahedral geometry to the Zn(II) ion in deprotonated state (Fig. 1A), with the nitrogen atom of the sulfonamide moiety coordinated to Zn(II) and an extended network of hydrogen bonds, involving amino acid residues Thr199 and Glu106 (numbering system used for the human CA, isoform I), also participating to the anchoring of the inhibitor molecule to the metal ion [44]. The aromatic/heterocyclic part of the inhibitor interacts with hydrophilic and hydrophobic residues of the cavity.…”

“…For some of them, X-ray crystal structures of the encoded CAs were also determined, and in vitro and in vivo inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates have been reported [3,32,[74][75][76][77][78]. Although the bacterial CA inhibition studies are in their infancy at this moment, cloning of more bacterial genomes may lead to the discovery of genes and proteins which may have interesting applications both in the biomedical and biotechnological fields [3,32,44,74,75,78].…”