title: Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance.
abstract: BACKGROUND
  Clinically used antibiotics act through one of these four mechanisms: cell wall biosynthesis inhibition, inhibition of protein biosynthesis, interference with DNA and RNA synthesis and the folate pathway.
  
  
  OBJECTIVE
  The metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) widespread in microorganisms and present as three genetically distinct families may be considered for the design of antiinfective agents with a different mechanism of action compared to the clinically used antibiotics. CAs are crucial for the life cycle of the pathogen, interfering with pH regulation and biosynthetic processes in which CO2 or bicarbonate are substrates. CA inhibition was shown to lead to debilitation or growth defects of several pathogenic bacteria.
  
  
  METHODS
  CAs catalyzes the interconversion between carbon dioxide to bicarbonate, leading to the formation of protons, and thus affecting pH homeostasis. Several classes of CA inhibitors (CAIs) are known to date, among which the metal complexing anions, the unsubstituted sulfonamides, the dithiocarbamates, etc., which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere.
  
  
  RESULTS
  Effective inhibitors for many bacterial CAs belonging to the α-, β-, and γ-CA classes were detected, some of which inhibited bacterial growth in vivo. Few of the inhibitors investigated so far were also selective for the bacterial over the human CA isoforms, which may pose problems for their wide clinical applications.
  
  
  CONCLUSIONS
  Structure-based drug design campaigns might lead to the achievement of the desired selectivity/ potency for preferentially inhibiting bacterial but not the host CAs.
authors.affiliation: Istituto di Bioscienze e Biorisorse, CNR, via Pietro Castellino 111-80131 Napoli, Italy.
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.affiliation: 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.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure
chemical_list: D000900:Anti-Bacterial Agents; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases
keywords: Anions; Antibacterial; Antiinfective; CA inhibitors; Carbonic anhydrase; Drug-design; Hydratase activity; Inhibitor selectivity; Metalloenzymes; Pathogens; Selective inhibition; Sulfonamide