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Bioorg Med Chem Lett. 2017 Feb 1;27(3):490-495. doi: 10.1016/j.bmcl.2016.12.035. Epub 2016 Dec 12.

Sulfonamide inhibition profile of the γ-carbonic anhydrase identified in the genome of the pathogenic bacterium Burkholderia pseudomallei the etiological agent responsible of melioidosis.

Author information

1
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, Napoli, Italy.
2
Università degli Studi 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
School of Chemistry, University of New South Wales, Sydney, New South Wales 2052, Australia.
5
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; School of Chemistry, University of New South Wales, Sydney, New South Wales 2052, Australia; Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di ScienzeFarmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
6
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, Napoli, Italy. Electronic address: clemente.capasso@ibbr.cnr.it.

Abstract

A new γ-carbonic anhydrase (CA, EC 4.1.1.1) was cloned and characterized kinetically in the genome of the bacterial pathogen Burkholderia pseudomallei, the etiological agent of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. The catalytic activity of this new enzyme, BpsCAγ, is significant with a kcat of 5.3×105s-1 and kcat/Km of 2.5×107M-1×s-1 for the physiologic CO2 hydration reaction. The inhibition constant value for this enzyme for 39 sulfonamide inhibitors was obtained. Acetazolamide, benzolamide and metanilamide were the most effective (KIs of 149-653nM) inhibitors of BpsCAγ activity, whereas other sulfonamides/sulfamates such as ethoxzolamide, topiramate, sulpiride, indisulam, sulthiame and saccharin were active in the micromolar range (KIs of 1.27-9.56μM). As Burkholderia pseudomallei is resistant to many classical antibiotics, identifying compounds that interfere with crucial enzymes in the B. pseudomallei life cycle may lead to antibiotics with novel mechanisms of action.

KEYWORDS:

Acetazolamide; Burkholderia pseudomallei; Carbonic anhydrase; Drug resistance; Inhibitor; Sulfamate; Sulfonamide; γ-Class

PMID:
28025002
DOI:
10.1016/j.bmcl.2016.12.035
[Indexed for MEDLINE]

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