An overview of novel antimicrobial carbonic anhydrase inhibitors

Four different genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) are present in bacteria, α-, β-, γ- and ι-CAs. They play relevant functions related to CO₂, HCO₃^-/H⁺ ions homeostasis, being involved in metabolic biosynthetic pathways, pH regulation, and represent virulence and survival factors for bacteria in various niches. Bacterial CAs started to be considered druggable targets in the last decade, as their inhibition impairs survival, growth, and virulence of these pathogens.

Significant advances were registered in the last years for designing effective inhibitors of sulfonamide type for Helicobacter pylori α-CA, Neisseria gonorrhoeae α-CA, vacomycin-resistant enterococci (VRE) α- and γ-CAs, for which the in vivo validation has also been achieved. MIC-s in the range of 0.25-4.0 µg/mL for wild type and drug resistant N. gonorrhoeae strains, and of 0.007-2.0 µg/mL for VRE were observed for some 1,3,4-thiadiazole-2-sulfonamides, and acetazolamide was effective in gut decolonization from VRE.

Targeting bacterial CAs from other pathogens, among which Vibrio cholerae, Mycobacterium tuberculosis, Brucella suis, Salmonella enterica serovar Typhimurium, Legionella pneumophila, Porphyromonas gingivalis, Clostridium perfringens, Streptococcus mutans, Burkholderia pseudomallei, Francisella tularensis, Escherichia coli, Mammaliicoccus (Staphylococcus) sciuri, Pseudomonas aeruginosa, may lead to novel antibacterials devoid of drug resistance problems.