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An overview of novel antimicrobial carbonic anhydrase inhibitors

Journal

EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 27, Issue 10, Pages 897-910

Publisher

TAYLOR & FRANCIS LTD
DOI: 10.1080/14728222.2023.2263914

Keywords

Carbonic anhydrase; inhibitors; sulfonamides; Helicobacter pylori; antibiotic drug resistance; Neisseria gonorrhoeae; vacomycin-resistant enterococci

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Carbonic anhydrases play important roles in bacteria and targeting them could lead to the development of novel antibacterials without drug resistance problems. Significant advances have been made in designing effective inhibitors for various bacterial CAs, with in vivo validation for some pathogens.
Introduction: Four different genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) are present in bacteria, alpha-, beta-, gamma- and iota-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.Areas covered: Significant advances were registered in the last years for designing effective inhibitors of sulfonamide type for Helicobacter pylori alpha-CA, Neisseria gonorrhoeae alpha-CA, vacomycin-resistant enterococci (VRE) alpha- and gamma-CAs, for which the in vivo validation has also been achieved. MIC-s in the range of 0.25-4.0 mu g/mL for wild type and drug resistant N. gonorrhoeae strains, and of 0.007-2.0 mu g/mL for VRE were observed for some 1,3,4-thiadiazole-2-sulfonamides, and acetazolamide was effective in gut decolonization from VRE.Expert opinion: 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.

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