Antibacterial carbonic anhydrase inhibitors: an update on the recent literature

The clinically licensed drugs used as antibiotics prevent the microbial growth interfering with the biosynthesis of proteins, nucleic acids, microorganism wall biosynthesis or wall permeability, and microbial metabolic pathways. A serious, emerging problem is the arisen of extensive drug resistance afflicting most countries worldwide.

An exciting approach to fight drug resistance is the identification of essential enzymes encoded by pathogen genomes. Inhibition of such enzymes may impair microbial growth or virulence due to interference with crucial metabolic processes. Genome exploration of pathogenic and nonpathogenic microorganisms has revealed carbonic anhydrases (CAs, EC 4.2.1.1) as possible antibacterial targets.

Balancing the equilibrium between CO₂ and HCO₃ ^- is essential for microbial metabolism and is regulated by at least four classes of CAs. Classical CA inhibitors (CAIs) such as ethoxzolamide were shown to kill the gastric pathogen Helicobacter pylori in vitro, whereas acetazolamide and some of its more lipophilic derivatives were shown to be effective against vancomycin-resistant Enterococcus spp., with MICs in the range of 0.007-2 µg/mL, better than linezolid, the only clinically used agent available to date. Such results reinforce the rationale of considering existing and newly designed CAIs as antibacterials with an alternative mechanism of action.