Sulfonamide inhibition profiles of the β-carbonic anhydrase from the pathogenic bacterium Francisella tularensis responsible of the febrile illness tularemia

Bioorganic & Medicinal Chemistry
Sonia Del PreteClemente Capasso

Abstract

A new β-class carbonic anhydrase (CA, EC 4.2.1.1) has been cloned, purified and characterized in the genome of the pathogenic bacterium Francisella tularensis responsible of the febrile illness tularemia. This enzyme, FtuβCA, showed a kcat of 9.8 ×105s-1 and a kcat/KM of 8.9 ×107M-1s-1 for the CO2 hydration, physiological reaction, being one of the most effective β-CAs known to date, with a catalytic activity only 1.68-times lower than that of the human(h) isoform hCA II. A panel of 39 simple aromatic and heterocyclic sulfonamides, as well as clinically used drugs incorporating sulfonamide/sulfamate zinc-binding groups, was used to investigate the inhibition profile of FtuβCA with these classes of derivatives. The enzyme generally showed a weaker affinity for these inhibitors compared to other α- and β-CAs investigated earlier, with only acetazolamide and its deacetylated precursor having inhibition constant <1µM. Indeed, the two compounds acetazolamide AAZ and its deacetylated precursor 13 (KIs of 655-770nM), as well as metanilamide and methazolamide (KIs of 2.53-2.92µM), were the best FtuβCA inhibitors detected so far. As the physiological role of bacterial β-CAs is poorly understood for the virulence/life cycle of these path...Continue Reading

Citations

Nov 16, 2017·Metabolites·Claudiu T Supuran, Clemente Capasso
Jul 6, 2018·Expert Opinion on Therapeutic Patents·Claudiu T Supuran, Clemente Capasso
Feb 7, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Atilla AkdemirClaudiu T Supuran
Jan 29, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Alessandra RogatoClemente Capasso
May 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andrea AngeliClaudiu T Supuran
Aug 14, 2020·Journal of Medicinal Chemistry·Jatinder KaurDaniel P Flaherty

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