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Sulphonamide inhibition profile of Staphylococcus aureus β-carbonic anhydrase.

ABSTRACT: This paper presents the production and kinetic and inhibitory characterisation of β-carbonic anhydrase from the opportunistic bacterium Staphylococcus aureus (SauBCA). From the eight different carbonic anhydrase (CA) families known to date, humans have only the α-form, whereas many clinically relevant pathogens have β- and/or γ-form(s). Based on this discovery, β- and γ-CAs have been introduced as promising new anti-infective targets. The results of this study revealed that recombinant SauBCA possesses significant CO₂ hydration activity with a k_cat of 1.46 × 10⁵ s^-1 and a k_cat/K_M of 2.56 × 10⁷ s^{- 1}M^-1. Its enzymatic function was inhibited by various sulphonamides in the nanomolar - micromolar range, and the K_i of acetazolamide was 628 nM. The best inhibitor was the clinically used sulfamide agent famotidine (K_i of 71 nM). The least efficient inhibitors were zonisamide and dorzolamide. Our work encourages further investigations of SauBCA in an attempt to discover novel drugs against staphylococcal infections.

SUBMITTER: Urbanski LJ

PROVIDER: S-EPMC7534311 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Sulphonamide inhibition profile of <i>Staphylococcus aureus</i> β-carbonic anhydrase.

Urbanski Linda J LJ Bua Silvia S Angeli Andrea A Kuuslahti Marianne M Hytönen Vesa P VP Supuran Claudiu T CT Parkkila Seppo S

Journal of enzyme inhibition and medicinal chemistry 20201201 1

This paper presents the production and kinetic and inhibitory characterisation of β-carbonic anhydrase from the opportunistic bacterium <i>Staphylococcus aureus</i> (SauBCA). From the eight different carbonic anhydrase (CA) families known to date, humans have only the α-form, whereas many clinically relevant pathogens have β- and/or γ-form(s). Based on this discovery, β- and γ-CAs have been introduced as promising new anti-infective targets. The results of this study revealed that recombinant Sa ...[more]

PMID: 32972256

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Project description:Sulphonamide adducts of three Co(II) carbonic anhydrases were investigated by e.p.r. (electron paramagnetic resonance) at helium temperatures. The highly anisotropic 9 GHz spectra exhibited only three distinct features, with g values between 6.3 and 1.5. Such spectra arise from an electronic state with effective spin S'=(1/2), indicating that the high-spin (S=3/2) ground level is split into two spin doublets differing in energy by an amount large compared with the microwave quantum, but small in relation to thermal energies at ambient temperature. This situation would occur in a tetrahedral system suffering a large rhombic distortion. Calculations based on this model accounted for apparent discrepancies in integrated spectral intensities, and yielded magnetic moments in good agreement with independent measurements, especially in the case of certain small Co(II) complexes resembling the enzyme adducts in their e.p.r. signals. Precise sets of g values, reflecting a particular co-ordination geometry, were found to be representative of each enzyme variant and the type of sulphonamide inhibitor, whether benzocyclic or heterocyclic. A series of substituted benzene sulphonamides bound to the same enzyme gave rise to closely similar spectra despite a wide range of pK(i) values. Thus benzocyclic and heterocyclic sulphonamides were evidently held in the active-site cleft in characteristic orientations irrespective of side chains that might considerably influence the total binding strength. Visible absorption spectra of various sulphonamide adducts at room temperature showed a similar pattern of inhibitor dependence to the e.p.r. spectra, suggesting a correspondence between the co-ordination structures in liquid and frozen solution. E.p.r. spectra of the sulphonamide complexes were remarkable not only for their range of g values, but also for their variations in line-width and spin-lattice relaxation behaviour. Addition of glycerol to the medium produced marked enhancement in resolution, owing to the creation of a more homogeneous frozen matrix. The non-uniform spin relaxation was probably a consequence of the large anisotropy in effective g tensor.

Dataset Information

Sulphonamide inhibition profile of Staphylococcus aureus β-carbonic anhydrase.

Publications

Sulphonamide inhibition profile of <i>Staphylococcus aureus</i> β-carbonic anhydrase.

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