Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells

Abstract

The gastric proton pump inhibitor lansoprazole, its active analog AG-2000, and omeprazole dose dependently inhibited urease activity extracted with distilled water from Helicobacterpylori cells; the 50%1 inhibitory concentrations were between 3.6 and 9.5 ,M, which were more potent than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. These compounds also inhibited urease activity in intact cells of H. pylori and Helicobacter mustelae but did not inhibit ureases from other bacteria, such as Proteus vulgaris, Proteus mirabilis, and Providencia rettgeri. The mechanism of urease inhibition was considered to be blockage of the SH groups of H. pylori urease, since SH residues in the enzyme decreased after preincubation with lansoprazole and glutathione or dithiothreitol completely abolished the inhibitory action. The SH-blocking reagents A -ethylmaleinide and idoacetamide were also examined for their inhibition of the urease activity; their 5W0 inhibitory tontentrations were 100-to 1,000-fold higher than those of lansoprazole. These results suggest that lansoprazole and omeprazole can potently and selectively inhibit H. pylori urease and that inhibition may be related to earlier findings indicating that these compounds have selective activity against HP growth.

The Complement Regulator CD46 Is Bactericidal to Helicobacter pylori and Blocks Urease Activity

“…Indeed, the current study clearly implicates CD46 as inhibitor of urease activity, and earlier findings by Nagata et al (1993) 38 suggested that inhibition of urease activity is lethal to H. pylori. In addition to UreA, the affinity columns and mass spectrometry also identified AhpC.…”

“…Urease activity assay. The method to measure urease activity has previously been described 38 . Briefly, bacteria at 10 8 CFU/ml were centrifuged, washed and resuspended with ice-cold de-gassed 20 mM sodium phosphate (pH 6.8).…”

“…Cell extracts of H. pylori J99 (10 8 bacteria/ml) was prepared as described previously 38 , and loaded onto an Talon metal affinity column (Clontech) conjugated with recombinant CD46. Fractions were eluted, separated on SDS-PAGE, stained…”

Synthesis, Characterization and Urease Inhibition Studies of Transition Metal Complexes of Thioureas Bearing Ibuprofen Moiety

“…These inhibitors generally divided into two classes, substrate structural analogs like hydroxamic acid (Kobashi K 1962,;Krajewska B 2009;Muri EMF 2003) and those which affect the mechanism of the reaction like phosphoramidat (Amtul Z 2002;Kot M 2001). Lansoprazole (Nagata K 1993), omeprazole (Kuehler TC 1995), thiol-compounds (Todd MJ 1989), quinines (Bundy LG 1973) and schiff base derivatives (Hanif M 2012) are reported as potent urease inhibitors.…”

Synthesis and antimicrobial activity of ciprofloxacin and norfloxacin permanently bonded to polyethylene glycol by a thiourea linker

“…Thiourea and its derivatives cannot be hydrolyzed by ureases of different origin 16,17 or they are inhibitors of these enzymes. 18 Therefore, the permanently bonded drug conjugates containing a thiourea-linking moiety are expected as stable molecules under biological conditions. Consequently, the prepared permanently bonded drug conjugates do not correspond to a delivery system, but represent original macromolecules carrying bioactive endgroups.…”