Helicobacter pylori is highly susceptible to bismuth, a heavy metal with antimicrobial activity linked to its effect on bacterial iron uptake. Three strains of H. pylori were analyzed for indicators of iron limitation following exposure to the MIC of colloidal bismuth subcitrate (MIC CBS ). Similar morphologic and outer membrane changes were observed following growth in iron-limiting medium and at the MIC CBS that inhibited the growth of all three strains. These changes, which were also observed for iron-limited bacteria, were alleviated by the addition of iron to the cultures. H. pylori ATP levels, reduced in iron-limiting medium, were below the limits of detection in two of the three strains following exposure to bismuth. The addition of iron partially restored bacterial ATP levels in these two strains, although not to normal concentrations. In contrast, exposure of the same strains to the MIC CBS failed to deplete intracellular levels of iron, which were significantly reduced by culturing in iron-limiting medium. Thus, the antimicrobial effect of bismuth and of iron limitation on H. pylori may be similar. However, the respective mechanisms of intracellular action would appear to be mediated by different pathways within the cell.Prior to the discovery of the link between Helicobacter pylori and peptic ulcer disease (10), ulcers were thought to result from abnormal levels of gastric acid secretion. Bismuth compounds, commonly prescribed for ulcers, were initially thought to act as a barrier to the digestive effects of stomach acid by coating the ulcer site (31). Instead, it appears that H. pylori is highly susceptible to bismuth compounds (39), and treatment with colloidal bismuth subcitrate (CBS) is associated with a reduction in bacterial numbers and a concurrent reduction in gastritis in vivo (37). Despite these findings, bismuth monotherapy often fails to completely eradicate these bacteria (13,43), an observation that correlates with increasing ulcer relapse rates over time (34).The oldest regimen, an extremely effective one for clearing H. pylori infection, uses bismuth in combination with certain antibiotics (2, 51). Bismuth "triple therapy" consists of a bismuth compound (usually CBS or bismuth subsalicylate) in combination with metronidazole and tetracycline or amoxicillin (16) and reportedly cures 87.9% of patients within 1 week of treatment and 89.2% of patients within 2 weeks of treatment (49). H. pylori strains resistant to bismuth have not been reported and presumably arise at a lower frequency than strains resistant to antimicrobial agents such as nitroimidazoles, macrolides, and tetracycline (40). Bismuth compounds may reduce the development of resistance to coadministered antibiotics (27) and are also effective at treating H. pylori strains with established resistance to other antibiotics (3, 40). How bismuth is toxic to H. pylori is not known. A number of studies have linked the antimicrobial activities of many heavy metals, including bismuth, to their effects on iron uptake by bacteria (1,21,...

Thiopurine S-methyl transferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of the thiopurine immunosuppressants. To date, 22 variants have been identified that are predictive of decreased TPMT activity. In contrast, no molecular explanation has been found for the 1-2% of Caucasians who exhibit ultra-high TPMT activity. Here, we report the characterization of polymorphisms within a trinucleotide (GCC) repeat element of the TPMT promoter in two patients with inflammatory bowel disease exhibiting the highest TPMT activity from two testing centres. The first patient was heterozygous for a variant allele carrying seven GCC repeats [(GCC)7], whereas the second patient was heterozygous for a variant allele containing five GCC repeats [(GCC)5]. Fifty patients with inflammatory bowel disease with normal TPMT activity were all homozygous for six GCC repeats [(GCC)6]. Of 200 healthy controls, five were found to be heterozygous for the (GCC)7 variant. Within in vitro reporter gene assays, the mean luciferase activities of the (GCC)6, (GCC)7, and (GCC)5 constructs were 8.0+/-0.26, 13.2+/-0.10 and 12.3+/-0.12, respectively. The significant increase in activity observed for (GCC)5 and (GCC)7 compared with (GCC)6 (P-value

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