Developing Novel Bacterial Targets: Carbonic Anhydrases as Antibacterial Drug Targets

An interesting family of metalloenzymes is represented by the carbonic anhydrases (CAs, EC 4.2.1.1), ubiquitous enzymes present in prokaryotes and eukaryotes, divided into five genetically distinct classes: the α-, β-, γ-, δ-, and ζ-CA. All of them are metalloenzymes, using Zn(II), Cd(II), or Fe(II) ions at their active sites. These enzymes catalyze a very simple physiological reaction, the interconversion between carbon dioxide and bicarbonate ion and protons, being involved in crucial physiological processes. Bacteria encode CAs from at least three classes (the α-, β-, and γ) suggesting that these enzymes play an important role in their physiology. CAs are in fact involved in pH regulation in various compartments of the cell, transport of CO2 or HCO3-, supply of CO2 or HCO3- for the biosynthetic reactions (and thus metabolisms), degradation of enobiotics (e.g., cyanate), as well as in the survival and proliferation of intracellular pathogens within their host. CAs started to be investigated in detail only recently in pathogenic bacteria (e.g., Helicobacter pylori, Neisseria spp., Brucella spp., Mycobacterium tuberculosis, Vibrio cholerae, Salmonella enterica, etc.), in search of antibiotics with a novel mechanism of action as it has been demonstrated that in many of them, CAs are essential for the life cycle of the organism.