Inhibitors of Urease as Chemotherapeutic Agents

Rosenstein, Isobel J.; Hamilton‐Miller, J. M. T.; Musher, Daniel M.

doi:10.3109/10408418409105901

Cited by 56 publications

(37 citation statements)

References 63 publications

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“…Among the active iron chelates in this manuscript, acetohydroxamic acid is generally described as toxic to humans as it is an inhibitor of several key enzyme classes, including ureases, cyclo-oxygenases and carbonic anhydrase II. However, this toxicity is manifest only at high concentrations, and acetohydroxamic acid is prescribed under the trade name LithostatÔ as a urease inhibitor to treat patients with struvite kidney stones at high concentrations of 10-15 mg kg )1 day )1 (Rosenstein and Hamilton-Miller 1984). Intriguingly, iron supplementation is required in many cases (as a co-prescription with Lithostat) in order to circumvent iron deficiency as a result of acetohydroxamic acid treatment.…”

Section: Discussionmentioning

confidence: 99%

Chelated iron sources are inhibitors ofPseudomonas aeruginosabiofilms and distribute efficiently in anin vitromodel of drug delivery to the human lung

Musk¹,

Hergenrother²

2008

Journal of Applied Microbiology

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Aims: To determine whether chelated sources of ferric iron were efficient inhibitors of biofilm formation in Pseudomonas aeruginosa and might be suitable for drug delivery to the lungs of cystic fibrosis (CF) patients via nebulization. Methods and Results: The response of P. aeruginosa biofilms to elevated iron concentrations in the form of eight structurally varied iron chelators in a microtitre plate assay for biofilm production was examined in the lab. Among these iron chelates, picolinic acid and acetohydroxamic acid‐chelated iron were able to effectively thwart biofilm production in P. aeruginosa PA14 and in 20 clinical isolates of P. aeruginosa from a local hospital. The chelated iron sources showed excellent distribution in an Anderson cascade impactor model of particle size distribution in the human lung. Conclusions: Ferric picolinate and ferric acetohydroxamate are effective anti‐biofilm compounds against both lab and clinical strains of P. aeruginosa and are readily nebulized into particles of suitable size for lung delivery. Significance and Impact of the Study: The data herein serve both to solidify the growing base of literature correlating high iron levels with biofilm inhibition in P. aeruginosa and to highlight the potential of these chelators as nebulized agents to combat biofilms of P. aeruginosa in CF patients.

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Section: Discussionmentioning

confidence: 99%

Chelated iron sources are inhibitors ofPseudomonas aeruginosabiofilms and distribute efficiently in anin vitromodel of drug delivery to the human lung

Musk¹,

Hergenrother²

2008

Journal of Applied Microbiology

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“…Bacterial urease may be a contributing factor in the development of pyelonephritis (5,16,22), hyperammonemia (23), and catheter encrustation (20), as well as kidney and bladder stone formation (9,21). In the last case, ammonia generated from urea hydrolysis alkalinizes urine, resulting in the precipitation of polyvalent anions and cations in the form of struvite and apatite salts (9).…”

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confidence: 99%

“…In the last case, ammonia generated from urea hydrolysis alkalinizes urine, resulting in the precipitation of polyvalent anions and cations in the form of struvite and apatite salts (9). Although stones may develop from other causes, it has been estimated that 20 to 40% of all urinary stones are due to urease-positive bacteriuria (21).…”

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confidence: 99%

Purification, characterization, and genetic organization of recombinant Providencia stuartii urease expressed by Escherichia coli

et al. 1988

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Recombinant urease from Providencia stuariii has been expressed in and purified from Escherichia coli, and the genetic organization of the structural genes has been determined. Urease expression was induced by urea and repressed by nitrogen-rich components in the medium. The urease protein was purified 331-fold by DEAE-Sepharose, phenyl-Sepharose, Mono-Q, and phenyl-Superose chromatographies with a 7.3% yield. The enzyme possessed a Km for urea of 9.3 mM and hydrolyzed urea at a V__ of 7,100 ,umol/min per mg. P. stuartii urease is composed of three polypeptides (Mrs, 73,000, 10,0000, and 9,000) denoted by a, j, and y. The native enzyme is best described as (al12-y2)2, based on a native Mr of 230,000, obtained by gel filtration chromatography, and on the Coomassie blue staining intensities of the individual subunits. Atomic absorption analysis of the pure protein revealed 1.9 ± 0.1 nickel ions per a%02'y2 unit. In vitro transcription-translation analysis of transposon insertion mutants of the recombinant urease demonstrated that the urease peptides are encoded on adjacent DNA sequences and transcribed as a polycistronic mRNA in the order 'y, J, and then a.

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“…The hydrolysis of the reaction products causes an abrupt overall pH increase, the major cause for the negative side effects of the action of urease both for human and animal health, and for agriculture. Urease inhibitors have also been proposed to control urea hydrolysis in soil [6][7][8][9][10][11][12][13][14][15][16]. In particular, compound with the P(X)-NH2 segment (X = O, S) have received considerable attention as urease inhibitors.…”

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Phosphorhydrazides as urease and acetylcholinesterase inhibitors: biological evaluation and QSAR study

2016

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step of organic nitrogen mineralization to produce ammonia and carbamate. The carbamate produced during this reaction spontaneously decomposes, at physiological pH, to give a second molecule of ammonia and bicarbonate [3][4][5][6]. The hydrolysis of the reaction products causes an abrupt overall pH increase, the major cause for the negative side effects of the action of urease both for human and animal health, and for agriculture. Urease inhibitors have also been proposed to control urea hydrolysis in soil [6][7][8][9][10][11][12][13][14][15][16]. In particular, compound with the P(X)-NH2 segment (X = O, S) have received considerable attention as urease inhibitors. The most effective inhibitors are substituted both thiophosphinicamide and phosphinicamide families. Many phosphoramide compounds are the most effective compounds currently available to retard the hydrolysis of urea fertilizer in soil and to decrease ammonia volatilization and nitrite accumulation in soils treated with urea. (Thio)phosphoramide inhibited urease by forming a chelated complex with the nickel ion in the active site of enzyme. Phosphoramide acts as urease inhibitors by coordinating itself to the nickel ions of active site [15]. The oxygen or sulfur atoms and amide group of the inhibitor molecule are engaged in the formation of a bridge between the Ni(1) and Ni(2) ions. In this work, we have compared the effectiveness of new (thio) phosphorhydrazide compounds (1-17) to inhibit jack bean urease toward (thio)phosphoramides. In addition, we carried out quantitative structure-activity relationship (QSAR) studies on the aforementioned derivatives to gain an understanding of the activity shown by such compounds, to propose its union mode to the urease active site, and to try to create the correlation between the electronic and structural parameters in contrast to the inhibition potency.Abstract New phosphorhydrazide compounds (1-7, 13, 15-16) and thiophosphorhydrazide (14 and 17) were synthesized and characterized by 31 P, 13 C, 1 H NMR and IR spectroscopy. Furthermore, the crystal structure of compound (C 6 H 5 NH)(C 6 H 5 O)P(O)(NH-NH 2 ) (2) was investigated. The activities of derivatives on acetylcholinesterase (AChE) and urease were determined. Quantitative structure-activity relationship (QSAR) was used to understand the relationship between molecular structural features and inhibitory. DFT-QSAR models for enzymes demonstrated the importance of E LUMO parameter in describing the antiAChE and anti-urease activities of the synthesized compounds. The correlation matrix of QSAR models and docking analysis confirmed that electrophilicity descriptor can control the influence of the polarizability properties of N-H functional group of PAH derivatives in the inhibition of enzymes.

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Inhibitors of Urease as Chemotherapeutic Agents

Cited by 56 publications

References 63 publications

Chelated iron sources are inhibitors ofPseudomonas aeruginosabiofilms and distribute efficiently in anin vitromodel of drug delivery to the human lung

Chelated iron sources are inhibitors ofPseudomonas aeruginosabiofilms and distribute efficiently in anin vitromodel of drug delivery to the human lung

Purification, characterization, and genetic organization of recombinant Providencia stuartii urease expressed by Escherichia coli

Phosphorhydrazides as urease and acetylcholinesterase inhibitors: biological evaluation and QSAR study

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