Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.3.4.6 (urease)
7,490 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the inhibitory effects of four gastric proton pump inhibitors (PPIs): rabeprazole, a novel benzimidazole PPI, omeprazole, lansoprazole and AG-2000, on the urease activity of Helicobacter pylori (H. pylori). Their 50% inhibitory concentrations (I50s) were found to be 0.29, 5.4, 9.3 and 0.3 microM respectively. Rabeprazole and omeprazole were also potent inhibitors of Jack bean and Proteus mirabilis cellular ureases. The thioether derivative of rabeprazole, one of its metabolites, had no inhibitory effect on H. pylori urease, despite being reported as a more potent inhibitor of H. pylori growth than rabeprazole. The inhibitory effect of rabeprazole was prevented completely and reversed considerably by the addition of sulfhydryl compounds, such as beta-mercaptoethanol, glutathione and dithiothreitol. Moreover, the addition of beta-mercaptoethanol recovered the urease activity inhibited by rabeprazole. From these results, we expected that rabeprazole inhibited H. pylori urease activity by forming disulfide bonds between it and the active site of the enzyme.
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PMID:Helicobacter pylori urease inhibition by rabeprazole, a proton pump inhibitor. 853 94

The proton pump inhibitors (PPIs) omeprazole and lansoprazole and the acid-activated analog of lansoprazole AG-2000, which potently inhibit the urease of Helicobacter pylori (K. Nagata, H. Satoh, T. Iwahi, T. Shimoyama, and T. Tamura, Antimicrob. Agents Chemother. 37:769-774, 1993), also inhibited the urease activities of cell-free extracts as well as intact cells of Ureaplasma urealyticum. The 50% inhibitory concentrations were between 1 and 25 microM. These compounds also inhibited the ATP synthesis induced by urea in ureaplasma cells. The 50% inhibitory concentrations for ATP synthesis were close to those for urease activity, but they were lower than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. In addition, one of the metabolites of lansoprazole found in human urine, M-VI, also inhibited ureaplasmal urease activity and the ATP synthesis induced by urea at almost the same concentrations as those of lansoprazole. The inhibition of PPIs against ureaplasma urease was very similar to those against H. pylori urease, suggesting that the inhibitory mechanism against these ureases was due to the blockage of the SH residues on the cysteine of the enzyme. Omeprazole, lansoprazole, AG-2000, and M-VI inhibited the growth of U. urealyticum. Since ureaplasma urease is thought to be involved in the pathogenicity of this organism in the urogenital tract, PPIs and their analogs may be useful as chemotherapeutic agents against diseases caused by U. urealyticum.
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PMID:Growth inhibition of Ureaplasma urealyticum by the proton pump inhibitor lansoprazole: direct attribution to inhibition by lansoprazole of urease activity and urea-induced ATP synthesis in U. urealyticum. 861 64

This study investigated how pH and the presence of urea affect the survival and growth of Helicobacter pylori and whether these factors affect susceptibility to antibiotics in vitro. The viability of a wild-type strain and a urease-deficient mutant of H. pylori was studied after incubation for 1 h in buffers at different pH values at 37 degrees C under microaerophilic conditions. Viable counts were not affected at pH 5 and pH 7. In buffer at pH 3, there were no viable organisms, but urea (6.25 mM) protected the wild-type strain, which survived well. At pH 9, urea further reduced the viability of H. pylori and flurofamide almost abolished the effect of urea on the wild-type strain. Neither urea nor flurofamide affected the viability of the urease-deficient mutant under the same conditions. Growth was also pH dependent and was enhanced in shake-cultures. At pH 5, urea supported growth of the wild-type strain, but at pH 7 a toxic effect on the bacteria was observed. Growth of H. pylori at pH 5.9 was poor, and susceptibility to amoxycillin, erythromycin and clarithromycin was markedly less than at pH 7.2 and 7.9. The bactericidal activities of metronidazole and tetracycline were similar at the different pH values studied. At neutral pH the killing rates of amoxycillin and clarithromycin were growth rate dependent. Susceptibility to metronidazole was enhanced in stationary cultures. The interaction obtained between the proton pump inhibitor, omeprazole, and amoxycillin at pH 7 was of additive type. These results suggest that pH and growth conditions may be important in the antibacterial efficacy of different antibiotics in vivo and also provide a possible explanation for the potentiating effect of omeprazole with antibiotics in the treatment of H. pylori infections.
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PMID:Factors affecting growth and antibiotic susceptibility of Helicobacter pylori: effect of pH and urea on the survival of a wild-type strain and a urease-deficient mutant. 863 59

Recent international consensus statements have concluded that Helicobacter pylori is a causal factor in peptic ulcer disease and a Group 1 carcinogen in humans, and that all patients with peptic ulcer associated with H. pylori infection should receive eradication therapy. There are marked differences in the presentation of peptic ulcer disease between Japanese patients and those from other countries, however, and thus a committee of the Japanese Society of Gastroenterology has been set up to develop guidelines for clinical trials in patients with gastric or duodenal ulcers associated with H. pylori. According to these guidelines, eradication therapy should normally consist of dual therapy with a proton pump inhibitor, such as omeprazole, and an antibiotic; a nitroimidazole can be added, however, if necessary. The diagnosis of H. pylori should be made on the basis of a positive culture of the organism or histological examination of gastric biopsies, together with a positive urease test or 13C-urea breath test. Eradication should be confirmed by the same means 4-6 weeks after treatment. Other research is investigating the relationship between H. pylori and gastric cancer, an important issue in view of the high incidence of this condition in Japan. There is evidence that the Mongolian gerbil may be a useful animal model to investigate this question.
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PMID:Helicobacter pylori in Japan. 872 10

Omeprazole and lansoprazole are proton pump inhibitors that have shown activity against Helicobacter pylori and other Helicobacter species when tested by agar dilution. Lansoprazole was more active against H. pylori than was omeprazole, and the activity was independent of urease production. Disk susceptibility tests and agar dilution MIC determinations were performed to investigate the effects of incubation under different sets of atmospheric conditions on H. pylori inhibition. Oxygen concentration was found to influence proton pump inhibitor activity in vitro, with higher concentrations leading to greater susceptibility. The method of testing is important in determining the anti-Helicobacter activity of proton pump inhibitors.
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PMID:Oxygen concentration influences proton pump inhibitor activity against Helicobacter pylori in vitro. 872 32

Urease is an important virulence factor of pathogenicity of gastric Helicobacter pylori. The inhibition of H. pylori urease by the novel proton pump inhibitor, rabeprazole, was investigated kinetically. It was found to act as an irreversible noncompetitive inhibitor of the enzyme. The inhibitory potency of rabeprazole was dependent on the pH of reaction mixture and its Ki values were 0.14 microM (pH 5.0), 0.34 microM (pH 7.0) and 6.10 microM (pH 8.5). Progressive inactivation of urease by rabeprazole initially proceeded according to pseudo-first-order kinetics with respect to the remaining enzymatic activity at pH 7.0 and 37 degrees C, with a second-order rate constant of 0.0017 microM-1 s-1. When the inactivation half-life was plotted versus the reciprocal of the rabeprazole concentration, a straight line was obtained with a slope of -3.12. From an Arrhenius-plot of the temperature-dependence of the inactivation (over the range of 5-37 degrees C), an activation energy of 13.2 kcal/mol was calculated. Recovery of activity was incomplete for H. pylori urease inhibited by rabeprazole, suggesting that the rabeprazole-urease complex is very stable.
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PMID:Kinetic studies of Helicobacter pylori urease inhibition by a novel proton pump inhibitor, rabeprazole. 885 Mar 2

Factors affecting the in vitro antibacterial activity of omeprazole were studied. Our data show that 3H-labeled omeprazole covalently bound to Helicobacter pylori and to other gram-negative and gram-positive bacteria. The compound was found to bind to a broad range of proteins in H. pylori, and at pH 5, binding was enhanced 15-fold compared with binding at pH 7. The bactericidal activity correlated to the degree of binding, and at pH 5, a pH at which omeprazole readily converts to the active sulfenamide form, beta-mercaptoethanol, a known scavenger of sulfenamide, and fetal calf serum, to which noncovalent protein binding of omeprazole is known to occur, reduced the level of binding and almost entirely abolished the bactericidal activity. At pH 7 the killing activities of omeprazole and structural analogs (e.g., proton pump inhibitors) were dependent on the time-dependent conversion (half-life) to the corresponding sulfenamide. The bactericidal activity exerted by the sulfenamide form at pH 5 was not specific for the genus Helicobacter. However, in brucella broth at pH 7 with 10% fetal calf serum, only Helicobacter spp. were susceptible to omeprazole, with MBCs in the range of 32 to 64 micrograms/ml, and MBCs for more stable proton pump inhibitors were higher. Wild-type H. pylori and its isogenic urease-deficient mutant were equally susceptible to omeprazole. Thus, the urease is not a lethal target for omeprazole action in H. pylori. In conclusion, the antibacterial activities of omeprazole and analogs are dependent on pH and the composition of the medium used. Thus, at a low pH in buffer, these compounds have a nonselective action, whereas in broth at neutral pH, the mechanism of action is selective for Helicobacter spp.
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PMID:In vitro antibacterial activity of omeprazole and its selectivity for Helicobacter spp. are dependent on incubation conditions. 885 82

Helicobacter pylori's powerful urease enzyme is essential for colonisation and adaptation to the acid milieu of the stomach. Eradication of infection with "standard triple therapy" abolishes the chronic immunological and inflammatory responses to H. pylori and, thus, cures gastritis and peptic ulcer. In vitro, proton pump inhibitors (PPI) are active against H. pylori with minimum inhibitory concentrations that compare favourably with bismuth salts. PPIs are also potent urease inhibitors, but because PPIs are also active against urease-negative mutant Helicobacter spp., it is unlikely that urease inhibition alone accounts for their anti-H. pylori activity. Early reports suggested that omeprazole monotherapy was able to eradicate H. pylori. This has not been confirmed by more comprehensive studies, which have shown that treatment with omeprazole is associated with a shift of infection from the antrum to the corpus. The explanation for this observation is unclear, but does not appear to be due to bacterial overgrowth. Raising the intragastric pH with a PPI lowers the minimum inhibitory concentration of the many antimicrobials, while decreasing the acid storage pool increases the intramucosal concentration. Dual therapy (omeprazole with either amoxycillin or clarithromycin) is a more logical and highly effective alternative to standard triple therapy, with fewer side effects and better patient compliance. However, H. pylori eradication regimens based on a PPI and two antimicrobials will be the first-line treatment for H. pylori gastritis and peptic ulcer in the future.
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PMID:The chemotherapeutic effects of H+/K+ inhibitors on Helicobacter pylori infection. 885 4

The anti-ulcer drugs that act as covalent inhibitors of the gastric acid pump are targeted to the gastric H+/K+ ATPase by virtue of accumulation in acid and conversion to the active sulfenamide. This results in extremely effective inhibition of acid secretion. Appropriate dosage is able to optimize acid control therapy for reflux and peptic ulcer disease as compared to H2 receptor antagonists. However, clinical data on recurrence show that Helicobacter pylori eradication should accompany treatment of the lesion. These drugs have been found to synergize with many antibiotics for eradication. The survival of aerobes depends on their ability to maintain a driving force for protons across their inner membrane, the sum of a pH and potential difference gradient, the protonmotive force (pmf). The transmembrane flux of protons across the F1F0 ATPase, driven by the pmf, is coupled to the synthesis of ATP. The internal pH of H. pylori was measured using the fluorescent dye probe, BCECF, and the membrane potential defined by the uptake of the carbocyanine dye, DiSC3 [5] at different pHs to mimic the gastric environment. The protonmotive force at pH 7.0 was composed of a delta pH of 1.4 (-84mV) and a delta potential difference of -131mV, to give a pmf of -215 mV. The effect of variations in external pH on survival of the bacteria in the absence of urea correlated with the effect of external pH on the ability of the bacteria to maintain a pmf. The effect of the addition of 5 mM urea on the pmf was measured at different medium pH values. Urea restored the pmf at pH 3.0 or 3.5, but abolished the pmf at pH 7.0 or higher, due the production of the alkalinizing cation, NH3. Hence H. pylori is an acid-tolerant neutrophile due to urease activity, but urease activity also limits its survival to an acidic environment. These data help explain the occupation of the stomach by the organism and its distribution between fundus and antrum. This distribution and its alteration by proton pump inhibitors also explains the synergism of proton pump inhibition and antibiotics such as amoxicillin and clarithromycin in H. pylori eradication.
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PMID:Acid, protons and Helicobacter pylori. 916 99

Proton pump inhibitors of the benzimidazole type exert a specific antibacterial activity against Helicobacter pylori in vitro. In the present study, the basis for this selectivity was investigated, and in particular, various factors affecting the in vitro antibacterial activity of sulfide analogs of benzimidazoles were studied. Upon preincubation of omeprazole for a period of up to 72 h in a buffer at pH 7, a product was formed that was bactericidal for H. pylori but had no effect on urease activity. Sulfide constitutes the main end product of degradation. The sulfide analog of omeprazole (H 168/22) exerted a bactericidal activity specifically against both resting (in buffer) and growing (in broth) Helicobacter spp., and time-kill in buffer at pH 5 was enhanced compared to that at pH 7. There was no or very low covalent binding of 3H-labeled H 168/22 to Helicobacter spp. or to other gram-negative and gram-positive bacteria. In the presence of fetal calf serum (FCS) under the same conditions, binding was only slightly lowered while the killing activity was markedly reduced, indicating a probably nonspecific interaction with proteins and/or protection of bacterial target(s) by FCS. Addition of H 168/22 (four times the minimum bactericidal concentration [MBC]) to exponentially growing H. pylori immediately stopped growth, and after an incubation period of 20 h viable counts were reduced by >7 log10. One-hour exposure of H. pylori to the drug followed by repeated washing retarded growth by about 2 h, indicating that the effect is reversible after short-term exposure. MICs and MBCs of various sulfide structures were lower than those obtained in broth after the addition of the corresponding sulfoxide. Thus, the MBC of the sulfide structure of omeprazole against 140 clinical isolates of H. pylori ranged from 8 to 32 microg/ml, compared to an MBC of omeprazole of 32 to 128 microg/ml. A similar potency was also recorded against other helicobacters. In conclusion, formation of sulfides of benzimidazoles in culture media is the reason for the selective antibacterial effect against H. pylori. The sulfides rapidly exerted a reversible antibacterial activity, which was specific against both resting and growing Helicobacter spp. without any covalent protein binding.
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PMID:Basis for the selective antibacterial activity in vitro of proton pump inhibitors against Helicobacter spp. 925 64


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