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Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans.

ABSTRACT: Urease is a nickel-dependent amidohydrolase that catalyses the decomposition of urea into carbamate and ammonia, a reaction that constitutes an important source of nitrogen for bacteria, fungi and plants. It is recognized as a potential antimicrobial target with an impact on medicine, agriculture, and the environment. The list of possible urease inhibitors is continuously increasing, with a special interest in those that interact with and block the flexible active site flap. We show that disulfiram inhibits urease in Citrullus vulgaris (CVU), following a non-competitive mechanism, and may be one of this kind of inhibitors. Disulfiram is a well-known thiol reagent that has been approved by the FDA for treatment of chronic alcoholism. We also found that other thiol reactive compounds (l-captopril and Bithionol) and quercetin inhibits CVU. These inhibitors protect the enzyme against its full inactivation by the thiol-specific reagent Aldrithiol (2,2'-dipyridyl disulphide, DPS), suggesting that the three drugs bind to the same subsite. Enzyme kinetics, competing inhibition experiments, auto-fluorescence binding experiments, and docking suggest that the disulfiram reactive site is Cys592, which has been proposed as a "hinge" located in the flexible active site flap. This study presents the basis for the use of disulfiram as one potential inhibitor to control urease activity.

SUBMITTER: Diaz-Sanchez AG

PROVIDER: S-EPMC6274061 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans.

Díaz-Sánchez Ángel Gabriel ÁG Alvarez-Parrilla Emilio E Martínez-Martínez Alejandro A Aguirre-Reyes Luis L Orozpe-Olvera Jesica Aline JA Ramos-Soto Miguel Armando MA Núñez-Gastélum José Alberto JA Alvarado-Tenorio Bonifacio B de la Rosa Laura Alejandra LA

Molecules (Basel, Switzerland) 20161126 12

Urease is a nickel-dependent amidohydrolase that catalyses the decomposition of urea into carbamate and ammonia, a reaction that constitutes an important source of nitrogen for bacteria, fungi and plants. It is recognized as a potential antimicrobial target with an impact on medicine, agriculture, and the environment. The list of possible urease inhibitors is continuously increasing, with a special interest in those that interact with and block the flexible active site flap. We show that disulfi ...[more]

PMID: 27898047

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Project description:BackgroundMedication guides are required documents to be distributed to patients in order to convey serious risks associated with certain prescribed medicines. Little is known about the effectiveness of this information to adequately inform patients on safe use.ObjectiveTo examine the readability, suitability, and comprehensibility of medication guides, particularly for those with limited literacy.DesignAssessments of suitability and readability of 185 medication guides, and a sub-study examining change in suitability and readability from 2006 to 2010 among 32 of the medication guides (Study 1); 'open book' comprehension assessment of medication guides (Study 2).SettingTwo general internal medicine clinics in Chicago, IL.PatientsFour hundred and forty-nine adults seeking primary care services, ages 18-85.MeasurementsFor Study 1, the Suitability Assessment of Materials (SAM) and Lexile score for readability. For Study 2, a tailored comprehension assessment of content found in three representative medication guides.ResultsThe 185 analyzed medication guides were on average 1923 words (SD = 1022), with a mean reading level of 10-11th grade. Only one medication guide was deemed suitable in SAM analyses. None provided summaries or reviews, or framed the context first, while very few were rated as having made the purpose evident (8 %), or limited the scope of content (22 %). For Study 2, participants' comprehension of medication guides was poor (M = 52.7 % correct responses, SD = 22.6). In multivariable analysis, low and marginal literacy were independently associated with poorer understanding (β = -14.3, 95 % CI -18.0 - -10.6, p < 0.001; low: β = -23.7, 95 % CI -28.3 - -19.0, p < 0.001).ConclusionCurrent medication guides are of little value to patients, as they are too complex and difficult to understand especially for individuals with limited literacy. Explicit guidance is offered for improving these print materials.

Dataset Information

Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans.

Publications

Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans.

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