Carbonic Anhydrase Inhibitors as Novel Antibacterials in the Era of Antibiotic Resistance: Where Are We Now?

Resistance to antibiotic treatment developed by bacteria in humans and animals occurs when the microorganisms resist treatment with clinically approved antibiotics. Actions must be implemented to stop the further development of antibiotic resistance and the subsequent emergence of superbugs. Medication repurposing/repositioning is one strategy that can help find new antibiotics, as it speeds up drug development phases. Among them, the Zn2+ ion binders, such as sulfonamides and their bioisosteres, are considered the most promising compounds to obtain novel antibacterials, thus avoiding antibiotic resistance. Sulfonamides and their bioisosteres have drug-like properties well-known for decades and are suitable lead compounds for developing new pharmacological agent families for inhibiting carbonic anhydrases (CAs). CAs are a superfamily of metalloenzymes catalyzing the reversible reaction of CO2 hydration to HCO3- and H+, being present in most bacteria in multiple genetic families (alpha-, beta-, gamma- and iota-classes). These enzymes, acting as CO2 transducers, are promising drug targets because their activity influences microbe proliferation, biosynthetic pathways, and pathogen persistence in the host. In their natural or slightly modified scaffolds, sulfonamides/sulfamates/sulamides inhibit CAs in vitro and in vivo, in mouse models infected with antibiotic-resistant strains, confirming thus their role in contrasting bacterial antibiotic resistance.