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

Sonia Del Prete; Daniela Vullo; Pietro Di Fonzo; Sameh M Osman; Zeid AlOthman; William A Donald; Claudiu T Supuran; Clemente Capasso

doi:10.1016/j.bmcl.2016.12.035

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

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

Authors

Sonia Del Prete¹, Daniela Vullo², Pietro Di Fonzo¹, Sameh M Osman³, Zeid AlOthman³, William A Donald⁴, Claudiu T Supuran⁵, Clemente Capasso⁶

Affiliations

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.

PMID: 28025002
DOI: 10.1016/j.bmcl.2016.12.035

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 k_cat of 5.3×10⁵s^-1 and k_cat/K_m 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 (K_Is 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 (K_Is 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Burkholderia pseudomallei / drug effects*
Burkholderia pseudomallei / enzymology
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Humans
Melioidosis / drug therapy*
Melioidosis / metabolism
Melioidosis / microbiology
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Anti-Bacterial Agents
Carbonic Anhydrase Inhibitors
Sulfonamides
Carbonic Anhydrases