Carbonic anhydrases from pathogens: Bacterial carbonic anhydrases and their inhibitors as potential antiinfectives

The main classes of clinically used antibiotics inhibit the bacterial growth interfering with the biosynthesis of proteins, nucleic acids, folate metabolism, or the formation of the microbe cell wall. Most of the existing clinical drugs are affected by the emerging phenomenon of antibiotic resistance, which can be overcome through the discovery and use of novel enzymes essentially involved in the central bacterial metabolism. In this scenario, a crucial physiologic reaction for the survival of microbes, as well as for all living organisms, is a pivotal reaction of the central bacterial metabolism: the CO2 hydration/dehydration reaction catalyzed by a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1) and categorized into seven genetically distinct families (or classes), named α-, β-, γ-, δ-, Ζ-, η-, and θ-CAs. These metalloenzymes are indispensable for maintaining the physiologic equilibrium of the dissolved CO2, H2CO3, HCO3-, and CO32-, which are metabolites essential for microbe biosynthesis and energy metabolism. In the last few years, numerous CAs belonging to the α-, β-, and/or γ-CA classes have been detected, cloned, and characterized in many pathogenic bacteria, and it has been demonstrated in vivo that pathogenic and nonpathogenic bacteria need functional CAs for their survival or for manifesting their virulence in the host. In this chapter, a collection of the kinetic parameters and the bacterial CA inhibition profiles with sulfonamides and their bioisosteres, and (in)organic anions is reported. These studies have highlighted the recent developments in the search for new antibacterial agents able to interfere with the growth and virulence of the microorganisms by inhibition of CAs encoded in their genomes. The present study is a starting point in the design of effective pathogenic bacteria CA inhibitors with potential use as antiinfectives.