Merck
  • Home
  • Search Results
  • Inhibition of the β-carbonic anhydrase from Streptococcus pneumoniae by inorganic anions and small molecules: Toward innovative drug design of antiinfectives?

Inhibition of the β-carbonic anhydrase from Streptococcus pneumoniae by inorganic anions and small molecules: Toward innovative drug design of antiinfectives?

Bioorganic & medicinal chemistry (2010-12-18)
Peter Burghout, Daniela Vullo, Andrea Scozzafava, Peter W M Hermans, Claudiu T Supuran
ABSTRACT

The Gram-positive bacterium Streptococcus pneumoniae is a human respiratory tract pathogen that contributes significantly to global mortality and morbidity. It was recently shown that this bacterial pathogen depends on a conserved β-carbonic anhydrase (CA, EC 4.2.1.1) for in vitro growth in environmental ambient air and during intracellular survival in host cells. Hence, it is to be expected that this pneumococcal carbonic anhydrase (PCA) contributes to transmission and pathogenesis of the bacterium, making it a potential therapeutic target. In this study, purified recombinant PCA has been further characterized kinetically and for inhibition with a series of inorganic anions and small molecules useful as leads. PCA has appreciable activity as catalyst for the hydration of CO(2) to bicarbonate, with a k(cat) of 7.4×10(5)s(-1) and k(cat)/K(m) of 6.5×10(7) M(-1)s(-1) at an optimum pH of 8.4. Inorganic anions such as chloride, bromide, iodide, cyanate, selenocyanate, trithiocarbonate, and cyanide were effective inhibitors of PCA (K(I)s of 21-98μM). Sulfamide, sulfamic acid, phenylboronic, phenylarsonic acid, and diethyldithiocarbamate showed inhibition constants in the low micromolar/submicromolar range (K(I)s of 0.61-6.68μM), whereas that of the sulfonamide acetazolamide was in the nanomolar range (K(I)s 89nM). In conclusion, our results show that PCA can effectively be inhibited by a range of molecules that could be interesting leads for obtaining more potent PCA inhibitors. PCA might be a novel target for designing antimicrobial drugs with a new mechanism of action.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium persulfate, BioXtra, ≥99%
Sigma-Aldrich
Sodium persulfate, BioUltra, ≥99%
Supelco
Fluoride ion solution for ISE, 0.1 M F-, analytical standard (for ion-selective electrodes)
Sigma-Aldrich
Sodium selenate, BioXtra
Supelco
Sodium carbonate concentrate, 0.1 M Na2CO3 in water, eluent concentrate for IC
Sigma-Aldrich
Sodium selenate, ≥95% (elemental analysis)
Sigma-Aldrich
Sodium nitrite, ReagentPlus®, ≥99.0%
Sigma-Aldrich
Sodium nitrite, anhydrous, free-flowing, Redi-Dri, ACS reagent, ≥97%
Sigma-Aldrich
Sodium nitrite, anhydrous, Redi-Dri, ReagentPlus®, ≥99.0%
Sigma-Aldrich
Sodium iodide, puriss., meets analytical specification of Ph. Eur., BP, USP, 99-100.5% (calc. to the dried substance)
Sigma-Aldrich
Sodium iodide, puriss. p.a., ≥99.0% (AT)
Sigma-Aldrich
Sodium fluoride, puriss., meets analytical specification of Ph. Eur., BP, USP, 98.5-100.5% (calc. to the dried substance)
Sigma-Aldrich
Sodium iodide, ACS reagent, ≥99.5%
Sigma-Aldrich
Sodium perchlorate, ACS reagent, ≥98.0%
Sigma-Aldrich
Sodium iodide, ReagentPlus®, ≥99%
Sigma-Aldrich
Sodium persulfate, reagent grade, ≥98%
Sigma-Aldrich
Sodium persulfate, purum p.a., ≥98% (RT)
Sigma-Aldrich
Phenylboronic acid, 95%
Sigma-Aldrich
Sodium iodide, ≥99.99% trace metals basis
Sigma-Aldrich
Sodium iodide, 99.999% trace metals basis
Sigma-Aldrich
Sodium fluoride, 99.99% trace metals basis
Sigma-Aldrich
Sodium iodide, AnhydroBeads, −10 mesh, 99.999% trace metals basis
Sigma-Aldrich
Sodium bicarbonate solution, solution (7.5%), sterile-filtered, BioReagent, suitable for cell culture
Supelco
Nitrite ion standard solution, 0.1 M NO2-, for ion-selective electrodes
Sigma-Aldrich
Sodium bicarbonate, BioXtra, 99.5-100.5%
Sigma-Aldrich
Sodium bicarbonate, powder, BioReagent, for molecular biology, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
Sodium chloride solution, 5 M in H2O, BioReagent, for molecular biology, suitable for cell culture
Sigma-Aldrich
Sodium bromide, BioXtra, ≥99.0%
Sigma-Aldrich
Sodium chloride solution, 5 M
Sigma-Aldrich
Sodium carbonate, BioXtra, ≥99.0%