title: Bacterial, fungal and protozoan carbonic anhydrases as drug targets.
abstract: BACKGROUND
  The carbonic anhydrases (CAs, EC 4.2.1.1), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, as well as in the growth and virulence of pathogens belonging to bacteria, fungi and protozoa.
  
  
  METHODS
  CAs belonging to at least four genetic families, the α-, β-, γ- and η-CAs, were discovered and characterized in many pathogens: i) Bacteria encode enzymes from one or more such families, which were investigated as potential drug targets. Inhibition of bacterial CAs by sulfonamides/phenol derivatives lead to inhibition of growth of the pathogen for Helicobacter pylori, Mycobacterium tuberculosis, Brucella suis; ii) Fungi encode for α- and β-CAs, and inhibitors of the sulfonamide, thiol or dithiocarbamate type inhibited the growth of some of them (Malassezia globosa, Candida albicans, Crytpococcus neoformans, etc) in vivo; and iii) Protozoa encode α-, β- or η-CAs. Sulfonamide, thiols and hydroxamates effectively killed such parasites (Trypanosoma cruzi, Leishmania donovani chagasi, Plasmodium falciparum) in vivo.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a 1 CNR, Institute of Biosciences and Bioresorces (IBBR) , via P. Castellino, 111, 80131, Napoli, Italy clemente.capasso@ibbr.cnr.it.
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.affiliation: b 2 University of Florence, Neurofarba Department, Section of Pharmaceutical Chemistry , Via U. Schiff 6, 5019 Sesto Fiorentino, Firenze, Italy claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D009181:Mycoses / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology; D011528:Protozoan Infections / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases
keywords: X-ray; antiinfective; bacteria; carbonic anhydrases; fungi; hydroxamate; inhibitors; pathogens; protozoa; sulfonamide; thiols