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Bioorg Med Chem. 2017 Jul 1;25(13):3555-3561. doi: 10.1016/j.bmc.2017.05.007. Epub 2017 May 6.

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

Author information

1
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, Napoli, Italy; Università degliStudi di Firenze, Dipartimento Di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
2
Università degliStudi di Firenze, Dipartimento Di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
3
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
4
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
5
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, Napoli, Italy. Electronic address: clemente.capasso@ibbr.cnr.it.

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 pathogens, the present study may constitute a starting point for the design of effective pathogenic bacteria CA inhibitors with potential use as antiinfectives.

KEYWORDS:

Carbonic anhydrase; Francisella tularensis; Inhibitors; Metalloenzymes; Sulfonamides; Tularemia; β-Class

PMID:
28511911
DOI:
10.1016/j.bmc.2017.05.007
[Indexed for MEDLINE]

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