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. 2000 Nov;44(11):3069–3073. doi: 10.1128/aac.44.11.3069-3073.2000

A Novel Action of the Proton Pump Inhibitor Rabeprazole and Its Thioether Derivative against the Motility of Helicobacter pylori

Nanako Tsutsui 1, Ikue Taneike 1, Tatsuki Ohara 1, Satoshi Goshi 1, Seiichi Kojio 1, Nobuhiro Iwakura 1, Hiroyuki Matsumaru 1,†, Noriko Wakisaka-Saito 1, Hui-Min Zhang 1, Tatsuo Yamamoto 1,*
PMCID: PMC101604  PMID: 11036024

Abstract

The motility of Helicobacter pylori was maximum at 37°C and at pH 6. A newly developed proton pump inhibitor, rabeprazole (RPZ), and its thioether derivative (RPZ-TH) markedly inhibited the motility of H. pylori. The concentrations of the drug necessary to inhibit 50% of the motility were 0.25, 16, 16, and >64 μg/ml for RPZ-TH, RPZ, lansoprazole, and omeprazole, respectively. No such inhibitory effects were observed with H2 blockers or anti-H. pylori agents. The motilities of Campylobacter jejuni and C. coli—but not those of Vibrio cholerae O1 and O139, Vibrio parahaemolyticus, Salmonella enterica serovar Typhimurium, and Proteus mirabilis—were also inhibited. Prolonged incubation with RPZ or RPZ-TH inhibited bacterial growth of only H. pylori, except for a turbid colony mutant. The results indicate that RPZ and RPZ-TH have a characteristic inhibitory effect against the motility of H. pylori (spiral-shaped bacteria), which is distinguished from that against bacterial growth.

Helicobacter pylori, which colonizes the gastric mucosa, is closely associated with gastritis and peptic ulcers (7, 17) and is even a bacterial risk factor for gastric cancer (9, 10, 24, 25, 27). For eradication of H. pylori, a combination therapy using an antiacid agent (proton pump inhibitor [PPI] or H2 blocker) and one or two anti-H. pylori agents (such as clarithromycin and amoxicillin) has been recommended (8). PPIs inhibit the H+, K+ ATPase of parietal cells. In addition to this, PPIs inhibit H. pylori cell growth (1, 6, 11, 14, 15, 23) as well as urease activity (16, 19, 26) in vitro.

H. pylori is a spiral-shaped, gram-negative bacterium with one or two turns along its axis. It has multiple (four to six) polar flagella, and exhibits strong motility (13). The motility conferred by the flagella is necessary for colonization of the gastric mucosa and development of gastritis by H. pylori (3, 4). In this study, we examined the effects of a newly developed PPI, rabeprazole (RPZ), and its thioether derivative (RPZ-TH) on the motility of H. pylori.

MATERIALS AND METHODS

Bacterial strains.

H. pylori strains used (seven strains) were isolates from gastric biopsy specimens of patients with gastritis and peptic ulcers. The primary cultures of each isolate were stored frozen at −80°C in 3% skim milk (Difco Laboratories, Detroit. Mich.) supplemented with 5% glucose (Difco). The following motile, gram-negative bacteria were also employed: Campylobacter jejuni and Campylobacter coli for spiral-shaped bacteria; Vibrio cholerae O1 biotype El Tor strain EO8 (28), V. cholerae O1 biotype classical strain CI3 (28), and V. cholerae O139 strain T16 (30) for curved rods; and V. parahaemolyticus (e.g., strain 100B [29]), Salmonella enterica serovar Typhimurium, and Proteus mirabilis for rods. All bacterial strains except for P. mirabilis were isolates from patients with diarrhea.

Media and bacterial growth.

H. pylori, C. jejuni, and C. coli were grown on blood agar plates (Trypticase soy agar supplemented with 5% sheep blood; Becton Dickinson, Tokyo, Japan) for 2 (for C. jejuni and C. coli) to 4 (for H. pylori) days at 37°C in a microaerophilic atmosphere (10% O2 and 10% CO2). The colonies developed were then suspended in brain heart infusion (BHI) broth (Difco) containing 10% fetal bovine serum (FBS) (Gibco, Gaithersburg, Md.), followed by incubation for 18 to 20 h at 37°C in a microaerophilic atmosphere. The bacterial cultures were subjected to motion analysis. The other bacteria were grown in BHI broth at 37°C to log phase.

Anti-acid agents and antimicrobial agents.

PPIs used were omeprazole (OPZ), lansoprazole (LPZ), and RPZ (6, 26). RPZ-TH (6, 26), which is secreted into gastric juice, was also used. H2 blockers and anti-H. pylori agents used, respectively, included cimetidine, ranitidine, and famotidine and clarithromycin (CAM), amoxicillin (AMPC), and metronidazole (MNZ). They were gifts from their manufacturers.

Motion analysis.

Bacterial motility was examined under an inverted, phase-contrast microscope with a microwarm plate (Kitazato Co., Tokyo, Japan) that regulates temperatures of specimens. The motility speed (in micrometers per second) was measured by using a motion analysis system with the program C-Imaging C-MEN (Complix Inc., Cramberry, Pa.), essentially as described previously (18, 20). Bacterial swimming in a liquid layer of BHI broth containing 10% FBS between a glass slide and a glass cover (106 to 107 CFU/ml) was continuously recorded 15 times with a 0.05-s analysis time each (a total of 0.75 s), and the swimming speed (in micrometers per second) of each bacterial cell in a specimen was obtained. This was performed in at least five different fields of a specimen, the swimming speeds of ca. 300 bacterial cells were collected for each specimen, and the percent of motile bacteria was determined. Brownian motion of bacteria was estimated to be 0.4 ± 0.3 μm/s using heated or formalin-treated, nonmotile bacteria (H. pylori and V. cholerae), and the mean speed of ≥4.0 μm/s (speed 10 times higher than that of Brownian motion) was judged as positive motility; bacterial motility was also judged with the naked eye under a phase-contrast microscope. The swimming speed given in the text represents the mean speed of motile bacteria.

In the case of V. cholerae O1 and O139, since bacteria were strongly attached to the surface of the glass, glass that was coated with 3-aminopropyltriethoxysilane (9 Å in thickness) was purchased (Matsunami Co., Tokyo). This was further coated with FBS prior to use (to prevent bacterial attachment), and then used for the analysis. Data were evaluated using Student's t test, and P values of <0.05 were considered significant.

Susceptibility testing.

Susceptibility testing of H. pylori and other bacterial strains was performed using the agar dilution method with BHI agar containing 10% FBS according to previous procedures (12). Bacteria grown on 5% sheep blood agar plates were suspended in BHI broth containing 10% FBS at a concentration of approximately 106 CFU/ml. Aliquots of the bacterial suspension (approximately 104 CFU per spot) were inoculated onto the surface of drug-containing agar plates. The plates were incubated for 2 (for C. jejuni and C. coli) to 3 (for H. pylori) days at 35°C in a microaerophilic atmosphere. For other bacteria, incubation was for 20 h at 35°C.

RESULTS

Effects of temperature and pH on H. pylori motility.

The motility of H. pylori was observed best at 37°C, and no detectable motility was observed at environmental temperatures (<20°C) (Fig. 1A). This was a marked contrast to the data of V. cholerae O1, which showed a temperature-independent manner of motility (Fig. 1A). Higher mean swimming speeds were observed at higher temperatures (Fig. 1B). The motility of H. pylori, which was lost at 20°C, was completely recovered when the temperature was raised to 37°C; the reversibility was observed even in the presence of chloramphenicol (which inhibits protein synthesis) at 100 μg/ml.

FIG. 1.

FIG. 1

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(A) Temperature-dependent and -independent manners of motility of H. pylori and V. cholerae O1. Bacteria were grown at 37°C and then suspended in BHI broth containing FBS (pH 7.4) prewarmed at the indicated temperatures. Symbols: open square, H. pylori strain C7M (results similar to those shown in the figure were also obtained with six other H. pylori strains); closed square, V. cholerae O1 strain EO8 (results similar to those shown in the figure were also obtained with V. cholerae O1 strain CI3). The data represent means ± standard deviations (error bars) of three trials. (B) Swimming speed of the motile bacteria shown in panel A.

The motility of H. pylori was also dependent on culture pH. When strain C7M was grown at pH 7.4 and suspended in fresh broth at pH 6.0 and pH 7.4, the percentages of motile bacteria were similar at both pHs (88 ± 7 versus 83 ± 8 μm/s), but the mean swimming speed was higher at pH 6.0 than at pH 7.4 (107 ± 12 versus 71 ± 8 μm/s; P < 0.05). A similar pH dependency was also observed with six other H. pylori strains.

Motility inhibition.

The anti-acid agent or anti-H. pylori agent was added to bacterial suspensions at a concentration of 16 μg/ml each at pH 7.4 and at 37°C, and the bacterial motility was examined immediately after the addition of the agent. RPZ and RPZ-TH markedly inhibited the motility of H. pylori (Fig. 2). The inhibitory effect of RPZ was similar to that of LPZ. RPZ-TH completely blocked the motility. In contrast, the anti-H. pylori agents AMPC, CAM, and MNZ and H2 blockers cimetidine, ranitidine, and famotidine had no effects.

FIG. 2.

FIG. 2

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The inhibitory effects of PPIs and the thioether derivative on the motility of H. pylori. The motility of H. pylori (seven strains) was examined at pH 7.4 and at 37°C in the presence (16 μg/ml) or absence of the indicated agent. The data were obtained immediately after the addition of the agent (within 15 s). The data represent means ± standard deviations (error bars) of seven H. pylori strains (three trials for each strain). ∗, P < 0.05.

Complete inhibition of the motility by RPZ-TH was observed at a concentration as low as 1 μg/ml (Fig. 3A). The concentrations of drug necessary to inhibit 50% of the motility were 0.25, 16, 16, and >64 μg/ml for RPZ-TH, RPZ, LPZ, and OPZ, respectively, at pH 7.4 (Fig. 3A). Similar inhibitory effects were also observed at pH 6.0 (Fig. 3B). Such motility inhibition was observed immediately after the addition of the agents, whereas the viability of the bacterial cells was not immediately affected (Fig. 4).

FIG. 3.

FIG. 3

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H. pylori motility at pH 7.4 (A) and pH 6.0 (B) in the presence of various concentrations of PPIs and the thioether derivative. H. pylori strains were suspended in a fresh liquid medium at pH 7.4 and pH 6.0, and then the motility was examined at 37°C in the presence or absence of the drug. The data were taken immediately after the addition of the agent (within 15 s), and means ± standard deviations (error bars) of the data from seven strains are shown. Symbols: closed triangle, OPZ; open triangle, LPZ; open square, RPZ; closed square, RPZ-TH.

FIG. 4.

FIG. 4

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Time course of the inhibition of H. pylori motility by PPIs and the thioether derivative. Bacterial suspensions (of H. pylori strain C7M) were incubated at 37°C in the presence (16 μg/ml) or absence of the drug, and portions of the samples were periodically taken and examined for motility (A) and viability (B). The bacterial viability was examined by plating the bacterial dilutions onto blood agar and counting colonies that developed after incubation. Symbols: open circle, without drug; open diamond, with OPZ; open triangle, with LPZ; open square, with RPZ; closed square, with RPZ-TH.

When the bacteria were exposed to RPZ-TH (16 μg/ml) for 10 min and then suspended in a fresh medium (BHI broth containing 10% FBS) and incubated at 37°C for 30 min, 80% of the bacteria became motile, indicating that the inhibitory effect of RPZ-TH on the H. pylori motility was reversible.

Inhibition of the bacterial motility by RPZ-TH and the PPIs was also observed with C. jejuni and C. coli (Table 1). In two of the four strains, RPZ-TH completely inhibited the motility, just like with H. pylori. However, no inhibitory effects were observed with V. cholerae O1 or O139, V. parahaemolyticus, P. mirabilis, or S. enterica serovar Typhimurium (Table 1).

TABLE 1.

Inhibitory effects of PPIs and the thioether derivative against the motility and growth of spiral-shaped, curved-rod-shaped, and rod-shaped bacteriaa

Bacterium and strain Inhibition of motility (%)b by:
MIC (μ/ml)c of:
OPZ LPZ RPZ RPZ-TH OPZ LPZ RPZ RPZ-TH
H. pylori
 I48B 14 33 41 100   16    2 0.5 0.25
 I49A 19 42 51 100    8    1 0.5 0.5
 I52A  8 23 28 100    8    1 0.5 0.25
 I52B 10 24 38 100    8    1 0.25 0.25
 I55B 12 16 19 100   16    2 0.5 0.5
 C7M <5 46 54 100   16    2 0.5 0.5
 I49B <5 <5 46 100    8    1 0.5 0.5
 I49Bm 11 44 37 100 ≥256 ≥256 ≥256 64
C. jejuni
 CJ1 <5 12 18  58 ≥256 ≥256 ≥256 ≥256
 CJ2  8 46 43 100 ≥256 ≥256 ≥256 ≥256
 CJ4 <5 25 30  65 ≥256 ≥256 ≥256 ≥256
C. coli
 CC1 <5 34 24 100 ≥256 ≥256 ≥256 ≥256
V. cholerae O1
 CI3 <5 <5 <5 <5 ≥256 ≥256 ≥256 ≥256
 EO8 <5 <5 <5 <5 ≥256 ≥256 ≥256 ≥256
V. cholerae O139
 T16 <5 <5 <5 <5 ≥256 ≥256 ≥256 ≥256
V. parahaemolyticus
 100B <5 <5 <5 <5 ≥256 ≥256 ≥256 ≥256
 VP1 <5 <5 <5 <5 ≥256 ≥256 ≥256 ≥256
P. mirabilis
 PM1 <5 <5 <5 <5 ≥256 ≥256 ≥256 ≥256
S. enterica serovar Typhimurium
 ST1 <5 <5 <5 <5 ≥256 ≥256 ≥256 ≥256
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a

Data are a representative of three experiments. 

b

Swimming motility was examined in BHI broth containing 10% FBS (pH 7.4) at 37°C. PPIs and the thioether derivative were added at a concentration of 16 μg/ml, and the inhibitory effects on motility were examined immediately. Swimming speeds (in micrometers per second) in the absence of drug were 60 to 90 for H. pylori, 90 to 100 for C. jejuni and C. coli, 90 to 100 for V. cholerae O1 and O139, 45 to 55 for V. parahaemolyticus, 20 to 30 for P. mirabilis, and 40 to 50 for S. enterica serovar Typhimurium. 

c

MICs were examined on BHI agar containing 10% FBS (pH 7.4) at 35°C (similar results showin in the table were also obtained at 37°C). 

Growth inhibition.

The MICs (μg/ml) of OPZ, LPZ, RPZ, and RPZ-TH for the seven H. pylori strains were 8 to 16, 1 to 2, 0.25 to 0.5, and 0.25 to 0.5, respectively (Table 1). RPZ was more active than LPZ. The activity of RPZ-TH was similar to or slightly greater than that of RPZ. A spontaneous mutant strain, I49Bm, whose motility was inhibited by PPIs and RPZ-TH similar to the parent strain I49B, was less susceptible to PPIs and RPZ-TH in MIC tests (Table 1). Strain I49Bm developed turbid colonies on agar plates instead of clear colonies (as in fresh isolates). PPIs and RPZ-TH had no inhibitory effects on the growth of C. jejuni and C. coli, V. cholerae O1 and O139, V. parahaemolyticus, P. mirabilis, and S. enterica serovar Typhimurium (Table 1).

DISCUSSION

Anti-H. pylori effects of PPIs have been reported. OPZ, LPZ, and RPZ inhibit the in vitro growth of H. pylori (1, 6, 11, 14, 15, 23) and in vitro urease activity (16, 19, 26). The inhibitory effects of OPZ and LPZ on the bacterial growth are found in H. pylori but not in other bacteria, including C. jejuni and Escherichia coli (11, 15). OPZ also inhibits the alcohol dehydrogenase activity of H. pylori (21). RPZ-TH, a thioether metabolite of RPZ that is secreted into gastric juice (unpublished data [Eisai Pharmaceutical Co. Ltd., Tokyo, Japan]), has an inhibitory effect on the in vitro growth of H. pylori, identical to or slightly greater than that of RPZ (6, 26). RPZ-TH, however, does not inhibit the in vitro urease activity of H. pylori (26).

The motility of H. pylori is an important virulence factor that plays a role in the colonization of the gastric mucosa (3, 4). In this study, we have demonstrated that the motility of H. pylori is strictly regulated by temperatures. H. pylori swam at a high speed at 37°C but ceased swimming at environmental temperatures (<20°C). Moreover, the motility of H. pylori was better under conditions of slightly acidic pH rather than neutral pH. Thus, it is concluded that H. pylori motility is well adapted to gastric circumstances.

In addition, we have unambiguously demonstrated that PPIs and a thioether derivative (RPZ-TH) have a strong inhibitory effect against the in vitro motility of H. pylori. The inhibitory effect was best observed with a thioether derivative of RPZ (RPZ-TH). The inhibitory effect of both RPZ and LPZ was moderate, and that of OPZ was very weak. It has been suggested that RPZ forms a very stable complex with H. pylori urease (19). The possibility exists that RPZ-TH tightly binds to the flagella or a bacterial surface molecule(s) associated with bacterial motility. If this is the case, such binding may be common to the spiral bacteria, since RPZ-TH also strongly inhibited the motility of C. jejuni and C. coli, but not V. cholerae, V. parahaemolyticus, S. enterica serovar Typhimurium, or P. mirabilis.

H. pylori, C. jejuni, and C. coli may have unique structures that could serve as targets of anti-spiral agents. For instance, we have shown that vitamin C inhibits the in vitro growth of H. pylori and C. jejuni but not V. cholerae, V. parahaemolyticus, S. enterica serovar Typhimurium, or E. coli (31).

RPZ-TH had its strongest inhibitory effects on both the motility and growth (as determined by the MIC assay) of H. pylori, although there was not a good correlation between the motility inhibition and the growth inhibition (the former was observed immediately after addition of the agent, and the latter was observed after prolonged incubation with the agent). The mechanisms of the inhibition of motility and bacterial growth by RPZ-TH seem distinctly different from each other, because (i) RPZ-TH, but not RPZ, totally blocked H. pylori motility, whereas the inhibition of H. pylori growth by RPZ-TH was similar to or only slightly better than that by RPZ and (ii) in the case of the mutant strain I49Bm and C. jejuni and C. coli, only motility (but not bacterial growth) was markedly inhibited.

The complete inhibition of H. pylori motility by RPZ-TH was observed at concentrations as low as 1 μg/ml, and the concentration of the drug necessary to inhibit 50% of the motility (for seven strains) was ca. 0.25 μg/ml. In addition, MICs of RPZ-TH for the H. pylori strains were 0.25 to 0.5 μg/ml. The concentration of RPZ-TH in gastric juice has been determined to be around 0.1 to 0.2 μg/ml (unpublished data [Eisai Pharmaceuticals Co., Ltd.]. Thus, RPZ-TH may interfere with the colonization by H. pylori of the gastric mucosa. This possibility is under investigation.

It has been shown that in patients undergoing H. pylori eradication treatment, H. pylori disappears from the antrum and can be found only in the corpus of the stomach (2, 5, 22). A further study is required to examine whether this consequence is more pronounced in treatment with RPZ than with other PPIs.

ACKNOWLEDGMENT

This study was supported in part by a grant from Ohyama Health Foundation Inc. (Tokyo, Japan).

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