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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, November 2000, p. 3069-3073, Vol. 44, No. 11
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
A Novel Action of the Proton Pump Inhibitor Rabeprazole and Its
Thioether Derivative against the Motility of Helicobacter
pylori
Nanako
Tsutsui,
Ikue
Taneike,
Tatsuki
Ohara,
Satoshi
Goshi,
Seiichi
Kojio,
Nobuhiro
Iwakura,
Hiroyuki
Matsumaru,
Noriko
Wakisaka-Saito,
Hui-Min
Zhang, and
Tatsuo
Yamamoto*
Department of Bacteriology, School of Medicine,
Niigata University, 757 Ichibanchou, Niigata, Japan
Received 26 April 2000/Returned for modification 7 June
2000/Accepted 3 August 2000
 |
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 mirabiliswere 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.
| |
INTRODUCTION |
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.
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FIG. 1.
(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.
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FIG. 2.
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).
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FIG. 3.
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.
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FIG. 4.
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).
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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
|
|
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).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Bacteriology, School of Medicine, Niigata University, 757 Ichibanchou, Asahimachidori, Niigata, Japan. Phone: 81-25-227-2050. Fax:
81-25-227-0762. E-mail:
tatsuoy{at}med.niigata-u.ac.jp.
Present address: Tsukuba University, Tsukuba, Ibaraki, Japan.
| |
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Abstract
Introduction
