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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, May 1999, p. 1072-1076, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro Anti-Helicobacter pylori
Activities of New Rifamycin Derivatives, KRM-1648 and
KRM-1657
Junko K.
Akada,1
Mutsunori
Shirai,1
Kenji
Fujii,2
Kiwamu
Okita,3 and
Teruko
Nakazawa1,*
Department of
Microbiology1 and First Department of
Internal Medicine,3 Yamaguchi University School
of Medicine, Ube, Yamaguchi 755-8505, and KANEKA Corporation,
Takasago Research Laboratories, Takasago, Hyogo
676-8688,2 Japan
Received 27 July 1998/Returned for modification 5 November
1998/Accepted 27 February 1999
 |
ABSTRACT |
The new rifamycin derivatives KRM-1657 and KRM-1648 were evaluated
for their in vitro antimicrobial activities against 44 strains of
Helicobacter pylori. Although the drugs were not very active against other gram-negative bacteria, the MICs at which 90% of
isolates are inhibited for these drugs were lower (0.002 and 0.008 µg/ml, respectively) than those of amoxicillin and rifampin for
H. pylori. Time-kill studies revealed that the bactericidal activities of these agents were due to cell lysis. The results presented here indicate that these new rifamycin derivatives may be
useful for the eradication of H. pylori infections.
| |
INTRODUCTION |
Helicobacter pylori is
associated with chronic gastritis and peptic ulcer disease (3,
12), as well as gastric carcinoma (20, 21). In
patients with mucosal H. pylori infection, eradication of
this microorganism seems to cure both infection and ulcer disease (18, 23). Although H. pylori is susceptible to
most antimicrobial agents in vitro, in vivo eradication of this
pathogen has been difficult (11). The highest cure rates
have required multidrug antimicrobial therapies, including those with
combinations of clarithromycin, metronidazole, or amoxicillin in
association with a proton pump inhibitor, e.g., omeprazole (8,
24). It has been reported, however, that the presence of strains
resistant to clarithromycin and metronidazole pre- and posttreatment
resulted in treatment failure (11, 13, 22), and thus, new
drugs with activity against H. pylori are crucial.
The recently synthesized rifamycin derivatives
3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin (KRM-1648)
and 3'-hydroxy-5'-(4-propyl-1-piperazinyl)benzoxazinorifamycin
(KRM-1657) (25, 28) exhibit potent activities against a
variety of gram-positive bacteria such as Mycobacterium
tuberculosis, Mycobacterium avium complex,
Staphylococcus aureus, Streptococcus pneumoniae,
and Streptococcus pyogenes (10). On the other
hand, these drugs have little activity against gram-negative bacteria
such as Escherichia coli, Klebsiella pneumoniae,
Haemophilus influenzae, and Neisseria gonorrhoeae
(9, 10).
In the present study, we determined the antibacterial activities of the
KRM compounds against H. pylori. Both KRM-1648 and KRM-1657
exhibited potent antimicrobial activities against clinical isolates of
H. pylori, a gram-negative bacterium.
| |
MATERIALS AND METHODS |
Antimicrobial agents.
KRM-1648, KRM-1657, and
14C-KRM-1648 (0.51 MBq/mg) were obtained from KANEKA Corp.
(Hyogo, Japan). Rifampin, amoxicillin, and clarithromycin were obtained
from Calbiochem (La Jolla, Calif.), Wako (Tokyo, Japan), and Taisho
Pharmaceutical Co., Ltd. (Tokyo, Japan), respectively. The antibiotics
were dissolved in dimethyl sulfoxide at 5.0 mg/ml (stock solution) and
were stored at 
20°C until use.
Bacterial strains and growth conditions.
H. pylori
NCTC11637 (the type strain) and 34 strains including strain HPK5 and
numbered CPY strains isolated from biopsy specimens from patients
undergoing upper gastrointestinal endoscopy at the University Hospital,
Yamaguchi University School of Medicine, Ube, Japan, were studied. Four
clarithromycin-resistant strains, three metronidazole-resistant
strains, and two strains resistant to both clarithromycin and
metronidazole were isolated in Oita Medical University, Oita, Japan,
and were also studied. The sources of these strains were patients with
gastric ulcers (20 strains), duodenal ulcers (6 strains),
gastroduodenal ulcers (2 strains), gastric cancer (8 strains), chronic
gastritis (6 strains), and duodenitis (1 strain). We used
Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) containing
5% (wt/vol) horse serum (Gibco BRL, Rockville, Md.) and solidified it
with 1.3% agar (Nakarai, Kyoto, Japan) to make an agar medium. The
bacteria were inoculated into 18-mm-diameter tubes containing 5 ml of
broth medium or into 25-ml flasks containing 10 ml of broth medium, and
the tubes and flasks were incubated at 37°C with shaking on a
rotating shaker (150 rpm) in a chamber filled with 15%
CO2. The agar plates were incubated in a gas mixture (10%
CO2, 5% O2, 85% N2) at 37°C for
4 days under high humidity.
MICs.
The MICs of KRM-1648, KRM-1657, rifampin, and
amoxicillin were determined in duplicate by the twofold serial agar
dilution method. Stock solutions were diluted in 0.1 M sodium-potassium phosphate buffer (pH 7.0) and were serially diluted with the buffer. Drug solutions with volumes equal to 1/10 the volume of the agar medium
were added to make drug-supplemented agar plates. Agar plates with drug
concentrations greater than 1 µg/ml were prepared by adding a stock
solution directly to the agar medium. Overnight cultures in 5 ml of
broth medium were adjusted to an optical density at 590 nm of 0.2, and
inocula were spotted onto drug-supplemented agar plates by using a
96-well inoculator. The bacterial counts in each spot (approximately 1 µl) were between 5 × 103 and 1 × 104 CFU (corresponding to 5 × 106 and
1 × 107 CFU/ml, respectively).
To determine the MICs at a lower pH, Muller-Hinton broth was adjusted
to pH 7.0 or pH 5.0 with HCl, solidified, autoclaved, and supplemented
with 1/20 the final volume of 5 horse serum and 1/10 the volume of the
drug solutions serially diluted with 0.1 M sodium-potassium phosphate
buffer (pH 7.0 or pH 5.0) to make the agar plates. The final pH values
were 7.4 and 5.4, as determined with broth medium without agar prepared
by the same procedure described above. Two of the several strains
tested showed satisfactory growth on the agar medium at pH 5.4.
Stability of KRM-1648 in an acidic environment.
To determine
the stability of KRM-1648 in medium with an acidic pH, 20 mg of
KRM-1648 dissolved in 200 ml of 0.01 N HCl (0.1 mg/ml; pH 2) in
duplicate was incubated at 37°C. After 1, 2, 5, 8, and 24 h, the
amounts of KRM-1648 in a 20-µl solution were determined by
high-pressure liquid chromatography.
Time-kill bactericidal activity studies.
Time-kill studies
were performed by the method of Coudron and Stratton (6, 7).
H. pylori HPK5 bacteria cultured overnight in 10 ml of broth
medium were inoculated at a density of 3 × 106 CFU/ml
into a 25-ml flask containing 10 ml of drug-supplemented broth medium.
At 0, 3, and 24 h, the samples were removed and serially diluted with
saline, 20-µl aliquots were spotted in duplicate onto agar plates,
the agar plates were incubated, and the numbers of CFU were determined.
The lowest level of accurate cell detection was 100 CFU/ml. In
addition, undiluted samples were spread onto glass slides and were Gram
stained to determine the cell morphology.
Antibiotic-resistant mutants.
The occurrence of spontaneous
antibiotic-resistant mutants was determined with six strains of
H. pylori. The bacteria were grown in 10 ml of broth medium
overnight; 1-ml aliquots of each culture containing approximately
108 bacteria were centrifuged, suspended in 0.2 ml of broth
medium, and plated onto drug-supplemented agar medium; and the plates were incubated for 4 days. In addition, the inoculum of each strain was
determined after appropriate dilution and plating on drug-free agar
plates. The number of bacterial colonies on agar plates was counted,
and the frequency of occurrence of spontaneous mutants was determined.
Resistant mutants were isolated by a single-colony isolation procedure
by streaking a colony once on the same drug-supplemented agar medium
followed by streaking of the colony on drug-free agar medium.
Incorporation of 14C-labeled KRM-1648 into H. pylori cells.
Measurement of the incorporation of KRM-1648
was performed as described previously (9). In brief,
H. pylori NCTC11637 and its KRM-1648-resistant mutant,
NCTC11637-K48r, which were grown in broth medium, were
inoculated into 10 ml of broth medium to an optical density at 590 nm
of 0.1. [14C]KRM-1648 (0.51 kBq/µmol) was added to a
final concentration of 1 µg/ml, and the reaction mixture was
incubated at 37°C. At indicated times, 1 ml of each of the incubated
suspensions was applied to a cellulose-nitrate filter (pore size, 0.45 µm; ADVANTEC, Tokyo, Japan); filtered; washed successively with
distilled water (30 ml), 0.5% trichloroacetic acid (30 ml), and 95%
ethanol (2 ml); and air dried. The radioactivity was then determined
with a Packard 3255 liquid scintillation counter. The incorporation experiment was performed in triplicate.
| |
RESULTS |
MICs of KRM-1648 and KRM-1657.
The MICs of KRM-1648, KRM-1657,
and rifampin for 44 H. pylori strains and those of
amoxicillin for 24 strains are presented in Fig.
1. KRM-1657 and KRM-1648 exhibited more
potent antimicrobial activities (MICs at which 50 and 90% of isolates
are inhibited [MIC50 and MIC90, respectively]
for KRM-1657, 0.001 and 0.002 µg/ml, respectively; MIC50
and MIC90 of KRM-1648, 0.004 and 0.008 µg/ml,
respectively) than amoxicillin (MIC50 and
MIC90, 0.031 and 0.063 µg/ml, respectively) and rifampin
(MIC50 and MIC90, 1 and 4 µg/ml,
respectively). When the MICs and the type of disease in the patient
from whom the strain was isolated were compared, there was no
correlation between the MICs and disease type for any drug (data not
shown). Clinically isolated strains that are resistant to
clarithromycin and/or metronidazole showed levels of susceptibility to
rifampin, KRM-1648, and KRM-1657 similar to those of the drug-sensitive
strains. An antimicrobial agent that is commonly used for the treatment
of H. pylori infection (clarithromycin) is known to be less
active at lower pH (5). In fact, as shown in Table
1, lowering of the pH resulted in a more
than eightfold increase in the MICs of clarithromycin. On the other
hand, the MICs of KRM-1648 and KRM-1657 did not change by lowering the
pH. We could not determine the MICs at pH values lower than 5.4 because
of the inability of most H. pylori strains to grow at those
pHs.
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FIG. 1.
Distribution of susceptibilities of 44 H. pylori strains to KRM-1657 ( ), KRM-1648 ( ), and rifampin
( ), and 24 strains to amoxicillin ( ).
|
|
Stability of KRM-1648 in an acidic environment.
To determine
the stability of KRM-1648 in the acidic stomach, we incubated KRM-1648
(0.1 mg/ml) at pH 2.0 and 37°C. After incubation for 8 and 24 h,
95.8 and 87% of the KRM-1648, respectively, remained, suggesting that
it is stable in an acidic environment.
Time-kill studies.
H. pylori HPK5 was inoculated in
broth medium containing various drugs at the MIC or at 10× the MIC,
and the CFUs were determined at 0, 3, and 24 h (Fig.
2). KRM-1657 at 0.001 µg/ml (1× the
MIC) produced a 1-log reduction in the numbers of CFU per milliliter relative to the numbers in the inoculum at 3 h and produced more than a 3-log decrease at 24 h. The numbers of CFU at 24 h in
the broth medium containing KRM-1657 at 0.01 µg/ml (10× the MIC) or KRM-1648 at 0.04 µg/ml (10× the MIC) were more than 4.5 logs lower than those in the control at 0 h, indicating the potent
bactericidal activities of the drugs. Rifampin at 2.5 µg/ml (10× the
MIC) also produced a 2-log reduction at 24 h, whereas amoxicillin
at 0.031 µg/ml (1× the MIC) and 0.31 µg/ml (10× the MIC) produced
only a 1-log decrease in the numbers of CFU per milliliter after
24 h.
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FIG. 2.
Time-kill bactericidal activities of amoxicillin,
rifampin, KRM-1648, and KRM-1657 at the MICs (0.031, 0.25, 0.004, and
0.001 µg/ml, respectively) and at 10× the MICs (0.31, 2.5, 0.04, and
0.01 µg/ml, respectively) against H. pylori HPK5.
|
|
Morphological studies performed by Gram staining revealed that cell
lysis occurred after incubation with 0.001 µg of KRM-1657 per ml for
24 h (Fig. 3B), whereas the control
culture did not show cell lysis (Fig. 3A). Similar morphological
changes were observed when the cells were incubated with 0.04 µg of
KRM-1648 per ml for 24 h (Fig. 3C). In contrast, amoxicillin
treatment produced coccoid forms. When the cells were incubated with
0.31 µg of amoxicillin per ml for 3 h, cell aggregates
consisting mostly of small coccoid forms formed (Fig. 3D). When the
cells were incubated with 0.031 µg of amoxicillin per ml for 24 h, large coccoid forms were predominant (Fig. 3E). Only a few coccoid
forms with irregular morphologies appeared among the KRM-treated cells.
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FIG. 3.
Gram staining of H. pylori HPK5 sampled from
the time-kill bactericidal activity test (Fig. 2). (A) No-drug control
at 24 h. A stationary-phase culture shows many spiral cells and a
few coccoid cells. (B) KRM-1657 (0.001 µg/ml; 1× the MIC) at 24 h. (C) KRM-1648 (0.04 µg/ml; 10× the MIC) at 24 h. (D)
Amoxicillin (0.31 µg/ml; 10× the MIC) at 3 h. (E) Amoxicillin
(0.031 µg/ml; 1× the MIC) at 24 h. Magnifications, ×1,000.
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|
Antibiotic-resistant mutants.
The frequency of occurrence of
spontaneous antibiotic-resistant mutants from six strains of H. pylori is presented in Table 2. The
concentrations of each drug used for selection were 50 µg/ml for
rifampin, 3.1 µg/ml for KRM-1648, 0.1 µg/ml for KRM-1657, and 3.1 µg/ml for amoxicillin. Colonies that grew on selective agar plates
were considered resistant to the respective drug. The frequencies of
occurrence of mutants resistant to KRM-1657, KRM-1648, and rifampin
were similar for a given strain but varied from strain to strain,
ranging from 2.0 × 10
6 to 1.9 × 108. No amoxicillin-resistant mutant appeared. We then
isolated mutant clones resistant to KRM-1657, KRM-1648, or rifampin,
and the MICs of these drugs were evaluated (Table 2). All mutant clones
selected on plates containing one of the rifamycin drugs was resistant to the other agents as well, indicating cross-resistance. On the contrary, no cross-resistance with rifamycin agents was seen for clarithromycin or amoxicillin (data not shown).
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TABLE 2.
Frequency of occurrence of spontaneous mutants in
H. pylori strains resistant to rifampin, KRM-1648, KRM-1657,
and amoxicillin and MICs for parental strain and mutant clone
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|
We could see some correlation between the MICs of rifampin and
selection frequency; selection frequencies for strains for which
rifampin MICs were lower, such as NCTC11637 and CPY3401, were lower,
while selection frequencies for strains for which MICs were higher,
such as CPY1124 and CPY3281, were higher. Such a correlation was not
observed with KRM-1648 or KRM-1657, which have potent antimicrobial activities.
Incorporation of [14C]KRM-1648 into H. pylori.
The cross-resistance among rifamycin agents suggested that
drug resistance is caused by point mutations in RNA polymerase, as for
other bacteria (16). However, previous results suggested the
involvement in gram-negative bacteria of a multidrug efflux system that
causes an apparent decrease in the level of drug incorporation (9). To see whether H. pylori NCTC11637 and a
KRM-1648-resistant clone (NCTC11637-K48r) have such an
efflux system, we determined the rate of incorporation of
[14C]KRM-1648 (Fig. 4). The
radioactivity of KRM-1648 in both the parental and the mutant cells
increased in a time-dependent manner, reaching ca. 1,800 to 2,000 dpm/mg (dry weight) during the first 1.5 h. Thus, the rifamycin
agent is incorporated irrespective of the resistance phenotype.
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FIG. 4.
Uptake of [14C]KRM-1648 by parental type
strain H. pylori NCTC11637 (open bars) and a
KRM-1648-resistant mutant (solid bars). Each bar indicates the
mean ± standard deviation of three determinations.
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| |
DISCUSSION |
Following the recognition of the important pathogenic role of
H. pylori infection in the development of gastroduodenal
diseases, there has been a continuous search for improved eradication
therapy. In the present study we tested the antimicrobial activities of newly synthesized rifamycin derivatives against 44 strains of H. pylori. The MIC90s of KRM-1657 and KRM-1648 were 0.002 and 0.008 µg/ml, respectively, which were lower than those of
amoxicillin (0.063 µg/ml; this study) (14), clarithromycin
(14), ciprofloxacin (14), tetracycline
(14), tobramycin (14), metronidazole (14), rifampin (4 µg/ml; this study), and rifaximin
(15). Time-kill studies revealed the antimicrobial
activities of the KRM compounds to be bactericidal, resulting in cell
lysis after incubation for 24 h with KRM-1657 at a concentration
0.001 µg/ml.
Several studies demonstrated that amoxicillin treatment of H. pylori can result in the development of coccoid forms (2, 4), as was also found in the present study. It has been
postulated that the coccoid forms are a nonculturable, dormant stage of
H. pylori and that they play a role in the survival of the
bacterium in hostile environments (1, 4, 26). Although the
coccoid forms induced by aerobiosis in the presence of a bactericidal antibiotic have been postulated to be a manifestation of cell death
(17), under microaerobic conditions the amoxicillin-induced coccoid form might not be such a manifestation. H. pylori is
highly susceptible to amoxicillin in vitro, but amoxicillin alone has little curative effect in clinical applications. The possibility remained, therefore, that the coccoid form, if induced in the stomach
by amoxicillin, might be viable and even infectious. In contrast to
amoxicillin, KRM-1657 and KRM-1648 do not induce a transition from the
spiral to the coccoid form. In addition, these agents appear to be
stable under acidic conditions, which may help to preserve their
antimicrobial activities in the stomach.
KRM-1648 is known to exhibit potent activity in vitro and in vivo
against gram-positive bacteria, but it is not generally effective
against gram-negative bacteria (10, 25). It is well established that the antimicrobial activity of rifamycin is due to
inhibition of microbial DNA-dependent RNA polymerases (9, 16). The mechanisms of action of the antimicrobial activity of
KRM-1648 against M. avium and E. coli have been
studied previously (9). RNA polymerases from M. avium and E. coli are similarly inhibited, but the
level of uptake of [14C]KRM-1648 by M. avium
is much greater than that by E. coli, possibly because
E. coli has AcrAB, a multidrug efflux system involved in
resistance to antibiotics such as 
-lactams, tetracycline, and
rifampin (19). We isolated spontaneous mutants resistant to
rifampin and showed that cross-resistance to KRM-1648 or KRM-1657 but
not to clarithromycin or amoxicillin occurred. In addition, radioactive
KRM-1648 was taken up by H. pylori NCTC11637 and by a
KRM-1648-resistant mutant at similar rates. These results are consistent with the assumption that the antimicrobial activities of
these KRM agents are due to their inhibitory actions on RNA polymerase.
Genomic sequencing of H. pylori 26695 revealed that the
genes encoding the and ' subunits of RNA polymerase are fused
and that an AcrB orthologue that is involved in the efflux of rifampin
in other bacteria is present (27). The extremely high degree
of susceptibility of H. pylori to KRM-1657 and KRM-1648 might be related to some unique features of the RNA polymerase and/or
to the specificity of the multidrug efflux system.
Taken together, the results presented here indicate that the new
rifamycin derivatives KRM-1657 and KRM-1648 are active against H. pylori at very low concentrations. Further studies are needed to
determine if these compounds can be used to eradicate H. pylori in vivo.
| |
ACKNOWLEDGMENTS |
This work was supported by a Grant-in-Aid for Scientific Research
(grant B08457089) from the Ministry of Education, Science, Culture, and
Sports of Japan.
We thank T. Fujioka, Oita Medical University, Oita, Japan, for the kind
gift of clarithromycin- and/or metronidazole-resistant strains of
H. pylori.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Microbiology, Yamaguchi University School of Medicine, 1144, kogushi, Ube, Yamaguchi 755-8505, Japan. Phone: 81-836-22-2226. Fax:
81-836-22-2227. E-mail:
nakazawa{at}po.cc.yamaguchi-u.ac.jp.
| |
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Antimicrobial Agents and Chemotherapy, May 1999, p. 1072-1076, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
