Bacterial, fungal and protozoan carbonic anhydrases as drug targets

Abstract

None of the microorganism CAs is validated as drug targets as yet, but the inhibitors designed against many such enzymes showed interesting in vitro/in vivo results. By interfering with the activity of CAs from microorganisms, both pH homeostasis as well as crucial biosynthetic reactions are impaired, which lead to significant antiinfective effects, not yet exploited for obtaining pharmacological agents. As resistance to the clinically used antiinfectives is a serious healthcare problem worldwide, inhibition of parasite CAs may constitute an alternative approach for obtaining such agents with novel mechanisms of action.

A new procedure for the cloning, expression and purification of the β-carbonic anhydrase from the pathogenic yeastMalassezia globosa, an anti-dandruff drug target

“…CAs are also found in plants, fungi, algae, protozoa, cyanobacteria and bacteria 8,[19][20][21][22][23][24][25] . Six different, genetically distinct CA families are known to date: a-, b-, g-, d-, z-and Z-CAs 8,20,22 . Many representatives of all these enzyme classes have been crystallized and characterized in detail.…”

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

“…Interestingly, γ-CAs use only CO 2 as substrate, while β-CAs can hydrolyze CO 2, H 2 S and COS [18]. Furthermore, α-CAs not only hydrate CO 2 , CS 2 but also possess esterase activity, with a range of esters of carboxylic, sulfonic or phosphate acids [6,9,11,17,19,20]. Generally, bacterial genome encodes for three CA classes that in agreement with the CA family nomenclature are designed as α, β and γ [17].…”

“…The CA classification uses Greek letters for the designation of the seven CA families known to date, i.e., the α, β, γ, δ, ζ η and θ-CAs [5][6][7][8][9][10]. Detailed biochemical, kinetic, phylogenetic and structural studies afforded a clear view regarding the differences between CA families.…”

“…The *Address correspondence to these authors at the Istituto di Bioscienze e Biorisorse, CNR, via Pietro Castellino 111-80131 Napoli, Italy; Tel:/Fax: +39-081-6132559/+39-081-6132558; E-mail: clemente.capasso@ibbr.cnr.it; Laboratorio di Chimica Bioinorganica, and Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Universita` degli Studi di Firenze, via della Lastruccia 3 -50019, Sesto Fiorentino, Firenze, Italy; Tel:/Fax: +39-055-4573729/+39-055-4573005; E-mail:claudiu.supuran@unifi.it catalytic function of CO 2 hydration is maintained for all CA classes, despite the diverse spatial reorganization of the active sites [5,[11][12][13][14][15][16]. In general the catalytic efficiency of the γ-, δ-and ζ-CAs is low compared to the β-and η-CAs, which in turn are less efficient catalysts compared to many bacterial α-CAs [6,9,11,17]. Interestingly, γ-CAs use only CO 2 as substrate, while β-CAs can hydrolyze CO 2, H 2 S and COS [18].…”

“…The metal ion from the enzyme active site is coordinated by three His residues in the α-, γ-,δ-and θ-classes, by one His, and two Cys residues in β-and ζ-CAs or by two His and one Gln residues in η-class with the fourth ligand being a water molecule/hydroxide ion acting as nucleophile in the catalytic cycle of the enzyme [9,12,17,25]. The α-, β-, δ-and, probably η-and θ-CAs use Zn(II) ions at the active site, γ-CAs are Fe(II) enzymes but they are active also with bound Zn(II) or Co(II) ions, whereas ζ-class uses Cd(II) or Zn(II) to perform the physiologic reaction catalysis [6,9,12,17,26,27]. The α-, β-, γ-and ζ-CAs have been crystallized, but not δ-, η-and θ-CAs.…”