In vivo action of novel alkyl methyl quinolone alkaloids against Helicobacter pylori

Kazunari Tominaga1,*, Kazuhide Higuchi1, Norio Hamasaki1, Masaki Hamaguchi1, Takashi Takashima1, Tetsuya Tanigawa1, Toshio Watanabe1, Yasuhiro Fujiwara1, Yasuhiro Tezuka2, Takema Nagaoka2, Shigetoshi Kadota2, Eiji Ishii3, Kazuo Kobayashi4 and Tetsuo Arakawa1

Departments of 1 Gastroenterology and 4 Host Defense, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585; 2 Research Institute for Traditional Sino-Japanese Medicines, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194; 3 Department of Health and Epidemiology, Osaka City Institute of Public Health and Environmental Sciences, 8-34 Tohjo-cho, Tennoji-ku, Osaka 543-0026, Japan

Received 14 February 2002; returned 30 April 2002; revised 6 June 2002; accepted 21 June 2002


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Previously purified and isolated compounds of novel alkyl methyl quinolone alkaloids (AM quinolones) from Gosyuyu (Wu-Chu-Yu), a Chinese herbal medicine, have a strong and highly selective antibacterial activity against Helicobacter pylori in vitro. To clarify the antibacterial mechanism(s) of AM quinolones, we examined the effects of AM quinolones on respiration of H. pylori in vitro. One week after treatment with AM quinolones alone (2, 10 or 20 mg/kg/day, orally) or combinations of AM quinolones and omeprazole (30 mg/kg/day) for H. pylori (1 x 108 cfu)-infected Mongolian gerbils, we checked viable H. pylori and myeloperoxidase (MPO) activity in the gastric tissues. AM quinolones decreased the number of H. pylori and inhibited H. pylori respiration in a dose-dependent manner. AM quinolones decreased the number of viable H. pylori (AM quinolones alone: 46.0 ± 22.6 x 104, 17.3 ± 4.9 x 104 and 8.1 ± 6.6 x 104 cfu/stomach, respectively; and combinations of AM quinolones and omeprazole: 8.0 ± 5.6 x 104, 4.2 ± 2.5 x 104 and 5.5 ± 2.7 x 104 cfu/stomach) compared with the vehicle-treated group (control: 359.9 ± 180.3 x 104 cfu/stomach). AM quinolones significantly decreased MPO activity of H. pylori-inoculated gastric tissues. These findings suggest that AM quinolones have a potent antibacterial effect against H. pylori through respiratory inhibition, and reduced bacterial growth in vivo. AM quinolones might be novel therapeutic agents for H. pylori eradication.

Keywords: H. pylori, alkyl methyl quinolones, eradication, respiration


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Recently, numerous studies have demonstrated that Helicobacter pylori infection is strongly associated with chronic active gastritis, peptic ulcers, mucosa-associated lymphoid tissue type lymphoma of the stomach and gastric carcinoma.13 Eradication therapy for H. pylori using various antibiotics such as metronidazole, amoxicillin or clarithromycin is now widely recognized to play a critical role in improving and/or preventing the above gastroduodenal diseases.46 However, eradication is not always successful and the use of these antibiotics occasionally causes the emergence of resistant colonies and various harmful adverse effects.7,8 The optimal therapeutic regimen for eradication of H. pylori is consequently controversial and still under investigation. There is thus a need for development of new therapeutic agents specifically targeted against H. pylori, which would represent a significant advance in the treatment of the infection.

Our previous studies demonstrated that, of numerous medical plants and spices, Gosyuyu, a crude extract from the fruit of Evodia rutaecarpa (E. rutaecarpa) and one component of Gosyuyu-to, a Chinese herbal medicine, had potent antibacterial activity against H. pylori in vitro, and that combination therapy including Gosyuyu-to, omeprazole and amoxicillin gave a better clinical eradication rate than dual therapy, without any significant adverse effects.9,10 In a previous study,11 we found that novel alkyl methyl quinolone alkaloids (AM quinolones): 1-methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone (Figure 1) were the strongest and highly selective antibacterial components of Gosyuyu against H. pylori. Their in vitro antibacterial activity against H. pylori was better than or similar to those of amoxicillin and clarithromycin. AM quinolones as well as amoxicillin or clarithromycin may thus be useful for the treatment of H. pylori infection. However, not only the antibacterial mechanism(s) but also the in vivo efficacy of AM quinolones are still unknown.



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Figure 1. The chemical structure of the novel AM quinolones 1-methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone.

 
In the present study, to clarify the antibacterial mechanism(s) of AM quinolones against H. pylori, we determined the effects of AM quinolones on H. pylori respiration in vitro. In addition, we examined whether AM quinolones can eradicate H. pylori and improve myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, of the gastric tissues of H. pylori-infected Mongolian gerbils.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bacterial strains and culture conditions

We used the standard H. pylori strain (ATCC 43504). H. pylori was grown on Brucella agar (Becton Dickinson Microbiological Systems, Franklin Lakes, NJ, USA) supplemented with 5% final concentration defibrinated horse blood (blood agar), or with bovine serum albumin (BSA) fraction V (A-4503; Sigma Chemical Co., St Louis, MO, USA) sterilized using a 0.2 µm filter at 0.5 mg/mL (albumin agar), with 0.1% final concentration ß-cyclodextrin (Kishida Chemicals Co., Osaka, Japan).11 Cells were cultured for 2 or 3 days at 37°C in a glove box (Forma Scientific Anaerobic System Model 1024; Rankin Biomedical Co., Clarkston, MI, USA) under humidified microaerophilic conditions including 80% N2, 15% CO2 and 5% O2. The colonies of H. pylori were suspended in Brucella broth including BSA. At the time of harvest, the bacteria had grown to an OD550nm of ~0.2, which corresponded to a viable cell concentration of 1 x 108 cfu/mL, and were in the early logarithmic growth phase, with good motility. The conditioned cells were used in the experiments described below.

Drug samples

Extraction and purification of the agents from the fruit of E. rutaecarpa purchased from Tsumura Company Ltd (Ibaraki, Japan) was carried out as described previously.11 In brief, the fruit of E. rutaecarpa was extracted twice with diethyl ether (300 mL x 2) under reflux for 2 h. The extracts were evaporated under reduced pressure. The diethyl ether extracts were separated into several fractions by preparative thin-layer chromatography (PTLC) with dichloromethane (first PTLC) as the solvent and then rechromatographed (second PTLC) with methanol:chloroform (2.5:97.5, v/v). Each fraction was detected by ultraviolet (253.7 nm) irradiation. Purification was repeated until a single spot was obtained on TLC. The compounds (AM quinolones) of 1-methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone, which could not be separated from each other, were obtained; we used the compounds (AM quinolones) in the subsequent studies.

Effects of AM quinolones on respiration of H. pylori

AM quinolones were added to Brucella broth containing H. pylori (1 x 108 cfu) at a dose of 0, 0.01, 0.1 or 1 mg/L and incubated. During incubation, oxygen consumption by H. pylori was monitored polarographically using a Clark-type oxygen electrode fitted to a 2 mL water-jacketed closed chamber at 37°C.12 The same experiments were performed repeatedly to confirm reproducibility.

Testing for eradication of H. pylori by AM quinolones in the gastric tissues of H. pylori-inoculated Mongolian gerbils

Mongolian gerbils (6 weeks old, male, 40–50 g) were purchased from Seac Yoshitomi Ltd (Fukuoka, Japan). Four weeks after H. pylori (1 x 108 cfu) inoculation, H. pylori-inoculated Mongolian gerbils were orally administered AM quinolones alone (2, 10 or 20 mg/kg), combined AM quinolones with omeprazole (30 mg/kg/day) or vehicle alone for 7 days. After 1 week of treatment, the stomach of each animal was excised and homogenized in Brucella broth containing BSA. Aliquots of dilutions of the homogenates were harvested on Brucella agar plates containing 5% horse blood at 37°C under microaerophilic conditions for 5 days. The number of colonies was counted and viable H. pylori were expressed as cfu/stomach. All experimental procedures were approved by the Animal Care Committee of Osaka City University Medical School.

Measurement of myeloperoxidase activity

MPO activity, a marker of neutrophil infiltration, of the gastric antral tissue was assayed by the method of Bradley et al.13 In brief, the gastric tissues were homogenized in 50 mM potassium phosphate buffer pH 6.0, containing 0.5% hexadecyltrimethylammonium bromide (Sigma Chemical Co.). Suspensions were then centrifuged and MPO in the resulting supernatant was assayed with a spectrophotometer (Beckman Instruments, Fullerton, CA, USA). One unit of MPO activity was defined as that degrading 1 µmol of peroxidase per minute at 25°C. Proteins were measured with a modified bicinchonic acid method with a BCA protein assay reagent kit (Pierce, Rockford, IL, USA). Results are expressed as units per mg protein.

Statistical analysis

All values are presented as mean ± S.E.M. Statistical significance was determined by two-way ANOVA, followed by the least-squares means test. Differences were considered significant at P < 0.05.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
MICs of AM quinolones were 0.02 mg/L for H. pylori reference strains (NCTC 11916 and NCTC 11637), and 0.05 mg/L for H. pylori ATCC 43504. MICs of AM quinolones for 17 strains of H. pylori patient isolates were 0.05 mg/L, while for the other four strains they were 0.02 mg/L. The MICs of AM quinolones for all H. pylori strains tested were lower than or similar to those reported previously for various antimicrobial agents such as amoxicillin and clarithromycin that are usually used to eradicate H. pylori in the clinical setting.14 After confirmation of all these findings, we used H. pylori strain ATCC 43504 in subsequent studies.

Effects of AM quinolones on respiration of H. pylori

AM quinolones inhibited the respiration of H. pylori in a dose-dependent manner: O2 consumption rates were 4.66 ± 0.21, 3.80 ± 0.09, 2.15 ± 0.05 and 2.12 ± 0.03 x 10–7 µmol/min/body for control, 0.01, 0.1 and 1 mg/L (20 x MIC noted above for H. pylori strain ATCC 43504) (Figure 2). However, AM quinolones had no effect on [3H]thymidine uptake into H. pylori (data not shown). High doses (0.1 and 1 mg/L) but not a low dose (0.01 mg/L (lower than the MIC noted above) of AM quinolones decreased the number of H. pylori over 24–72 h. However, AM quinolones had no cytotoxic effect on gastric epithelial cells (MKN-45) (data not shown). The target of the agents in vitro was suggested to be only H. pylori and not gastric epithelial cells.



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Figure 2. Effects of AM quinolones on respiration of H. pylori. Bar graphs show O2 consumption (10–7 µmol/min/body) of H. pylori (1 x 108 cfu) after incubation of AM quinolones at a dose of 0, 0.01, 0.1 or 1 mg/L. Each value represents the mean ± S.E.M. (n = 7). *P < 0.05 versus control (vehicle treated).

 
Effect of AM quinolones on the number of viable H. pylori in gastric tissues of inoculated Mongolian gerbils

After 1 week of treatment, the number of viable H. pylori in gastric tissues of inoculated animals decreased significantly (AM quinolones alone, at 2, 10 or 20 mg/kg/day: 46.0 ± 22.6 x 104, 17.3 ± 4.9 x 104 and 8.1 ± 6.6 x 104 cfu/stomach, respectively; combined AM quinolones at 2, 10 or 20 mg/kg/day with omeprazole at 30 mg/kg/day: 8.0 ± 5.6 x 104, 4.2 ± 2.5 x 104 and 5.5 ± 2.7 x 104 cfu/stomach, respectively) compared with the vehicle-treated group (control: 359.9 ± 180.3 x 104 cfu/stomach) (Table 1). During treatment, the agents caused no serious adverse effects such as diarrhoea, loss of appetite or body weight, and did not affect animal mortality. The presence of H. pylori in gastric tissues of treated Mongolian gerbils was histologically confirmed, and the scores of the presence of H. pylori by the updated Sydney System15 were consistent with the above-mentioned number of viable H. pylori in the gastric tissues.


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Table 1.  Effect of AM quinolones on the number of viable H. pylori in gastric tissues of inoculated Mongolian gerbils
 
Effect of AM quinolones on MPO activity in the gastric tissues of inoculated Mongolian gerbils

MPO activity of the H. pylori-infected gastric antral tissue with the vehicle treatment group (control) was 47.3 ± 10.8 units/mg protein (Figure 3). After 1 week of treatment with high-dose AM quinolones (20 mg/kg), MPO activity of the gastric tissue had decreased by 87.2%. In addition, combined AM quinolones (2, 10 or 20 mg/kg) and omeprazole treatment inhibited MPO activity by 83.1%, 69.0% or 80.3%, respectively. According to the updated Sydney System,15 histopathological grading for neutrophil infiltration was consistent with MPO activity in the gastric tissue of treated Mongolian gerbils.



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Figure 3. Effect of AM quinolones on MPO activity in the gastric antral tissues of inoculated Mongolian gerbils. MPO activity was assayed after 1 week of treatment with AM quinolones (2, 10 or 20 mg/kg) alone (open bars), combined AM quinolones (2, 10 or 20 mg/kg) with omeprazole (30 mg/kg/day) (hatched bars) or vehicle (control). Results are expressed as units per mg protein. Each value represents the mean ± S.E.M. (n = 3–6). *P < 0.05 versus control (vehicle treated).

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In the study reported herein, the AM quinolones exhibited a potent antibacterial effect against H. pylori mediated by respiratory inhibition but not DNA synthesis. In addition, AM quinolones significantly decreased the number of viable H. pylori in the stomachs of H. pylori-infected Mongolian gerbils with reduction of neutrophil infiltration and without causing harmful adverse effects including animal mortality.

Recent accumulating studies have yielded much knowledge of the basic metabolic pathways of H. pylori: the source of energy for H. pylori are metabolites of organic acids and amino acids obtained via the Krebs cycle; this energy is obtained by respiration; and H. pylori includes menaquinone-6 and an unidentified quinone as respiratory quinones.16,17 In addition, physiologically unfavourable conditions for H. pylori such as avoidance of its metabolic pathways and/or a lack of energy source result in transformation from the spiral to the coccoid form, which is dormant and not active.18,19 Thus, as one source of energy, respiration is a critical factor for H. pylori survival and/or growth in its life cycle. On the other hand, it has been reported that antimicrobial agents of the quinolone family competitively inhibit electron transport in the respiratory chain because of their structural similarity to microbial menaquinones.20,21 It was suggested that, given their characteristic chemical structure, AM quinolones inhibited respiration of H. pylori mediated by competitive inhibition of electron transport in the bacterial respiratory chain. Restriction of H. pylori growth associated with lack of energy caused by respiratory inhibition may be at least in part an antibacterial mechanism of AM quinolones.

The quinolone antimicrobial agents have been used clinically to prevent bacterial DNA synthesis by targeting two essential enzymes, DNA gyrase and DNA topoisomerase IV, that play important roles in DNA replication.22,23 However, in the present study, AM quinolones did not affect [3H]thymidine uptake into H. pylori. Urease activity is also a characteristic and essential property of H. pylori.24,25 In our other analysis using urea medium (Eiken Chemicals Co., Tokyo, Japan), AM quinolones did not affect urease activity. These findings suggest that the antibacterial activity of AM quinolones against H. pylori is mediated mainly by respiratory inhibition.

In in vivo studies, it is generally difficult to eradicate H. pylori, although many agents have potent antibacterial activity in vitro. Therefore, determination of both in vitro activity and in vivo efficacy is required for pharmacological evaluation of antimicrobial agents for treatment of H. pylori infection. In this study, AM quinolones decreased the number of viable H. pylori with reduction of neutrophil infiltration in the stomachs of H. pylori-inoculated animals. Although complete eradication was not achieved by the agents, their in vivo antibacterial activity was similar to or stronger than that of amoxicillin or clarithromycin alone.26,27 These findings indicate that AM quinolones exhibited in vivo efficacy as well as in vitro activity against H. pylori. Amoxicillin, clarithromycin and metronidazole are often used in therapeutic regimens for H. pylori eradication via their respective antimicrobial mechanism(s), such as inhibition of the organism’s cell membrane and associated protein synthesis of H. pylori. Recently, however, increased occurrence of clarithromycin- or metronidazole-resistant strains of H. pylori is frequently encountered, thereby causing serious problems. Thus, AM quinolones possessing novel and different antimicrobial mechanism(s) from the above representative antibiotics might be useful for H. pylori eradication therapy, although not all antimicrobial agents in the quinolone family have strong antibacterial activity against the microorganism.2830 In addition, interestingly, combined administration of AM quinolones with omeprazole was more potent than AM quinolones alone. Omeprazole is usually used clinically for H. pylori eradication therapy. According to the increase in in vivo efficacy induced by combination with omeprazole, AM quinolones are probably applicable for the clinical situation. Notably, we observed previously that AM quinolones were highly selective for H. pylori but not for other intestinal bacterial species.11 Together with the finding that AM quinolones had no direct cytotoxic effects on gastric epithelial cells in vitro, oral administration of AM quinolones might thus cause no serious adverse effects in vivo, such as diarrhoea, loss of appetite or body weight, and animal mortality. These observations together suggest that AM quinolones exhibit strong antibacterial activity without harmful adverse effects and could be a candidate for use in eradication therapy for H. pylori.

In conclusion, the AM quinolone compounds 1-methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone exhibited highly specific and strong antimicrobial activity against H. pylori mediated via respiratory inhibition without serious adverse effects. These agents, having a unique antimicrobial mechanism(s) different from that of other antibiotics such as amoxicillin, clarithromycin or metronidazole, may be beneficial in the treatment of H. pylori-associated gastroduodenal diseases, whether they are used alone or together with the above-mentioned antibiotics or proton pump inhibitor.


    Acknowledgements
 
This study was supported, in part, by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science and Culture in Japan.


    Footnotes
 
* Corresponding author. Tel: +81-6-6645-3811; Fax: +81-6-6645-3813; E-mail: tomy{at}med.osaka-cu.ac.jp Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Blaser, M. J. (1987). Gastric Campylobacter-like organisms, gastritis, and peptic ulcer disease. Gastroenterology 93, 371–83.[ISI][Medline]

2 . Marshall, B. J., Armstrong, J. A., McGechie, D. B. & Glancy, R. J. (1985). Attempt to fulfill Koch’s postulates for pyloric Campylobacter. Medical Journal of Australia 142, 436–9.[ISI][Medline]

3 . Parsonnet, J., Friedman, G. D., Vandersteen, D. P., Chang, Y., Vogelman, J. H., Orentreich, N. et al. (1991). Helicobacter pylori infection and the risk of gastric carcinoma. New England Journal of Medicine 325, 1127–31.[Abstract]

4 . Chiba, N., Rao, B. V., Rademaker, J. W. & Hunt, R. H. (1992). Meta-analysis of antibiotic therapy in eradicating Helicobacter pylori. American Journal of Gastroenterology 87, 1716–27.[ISI][Medline]

5 . Marshall, B. J., Goodwin, C. S., Warren, J. R., Murray, R., Blincow, E. D., Blackbourn, S. J. et al. (1988). Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet ii, 1437–42.[Medline]

6 . Rauws, E. A. J. & Tytgat, G. N. J. (1990). Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 335, 1233–5.[ISI][Medline]

7 . Adamek, R. J., Suerbaum, S., Pfaffenbach, B. & Opferkuch, W. (1998). Primary and acquired Helicobacter pylori resistance to clarithromycin, metronidazole, and amoxicillin—influence on treatment outcome. American Journal of Gastroenterology 93, 386–9.[ISI][Medline]

8 . Alarcón, T., Domingo, D., Prieto, N. & López-Brea, M. (2000). Clarithromycin resistance stability in Helicobacter pylori: influence of the MIC and type of mutation in the 23S rRNA. Journal of Antimicrobial Chemotherapy 46, 613–6.[Abstract/Free Full Text]

9 . Higuchi, K., Arakawa, T., Ando, K., Fujiwara, Y., Uchida, T. & Kuroki, T. (1999). Eradication of Helicobacter pylori with a Chinese herbal medicine without emergence of resistant colonies. American Journal of Gastroenterology 94, 1419–20.[ISI][Medline]

10 . Ishii, E. (1997). Genus Helicobacter pylori in stomach and antibacterial activity of natural materials against Helicobacter pylori. Gastroenterological Seminars 68, 143–52.

11 . Hamasaki, N., Ishii, E., Tominaga, K., Tezuka, Y., Nagaoka, K., Kadota, S. et al. (2000). Highly selective antibacterial activity of novel alkyl quinolone alkaloids from a Chinese herbal medicine, Gosyuyu (Wu-Chu-Yu), against Helicobacter pylori in vitro. Microbiology and Immunology 44, 9–15.[ISI][Medline]

12 . Nishikawa, M., Sato, E. F., Utsumi, K. & Inoue, M. (1996). Oxygen-dependent regulation of energy metabolism in ascites tumor cells by nitric oxide. Cancer Research 56, 4535–40.[Abstract]

13 . Bradley, P. P., Christensen, R. D. & Rothstein, G. (1982). Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood 60, 618–22.[Abstract]

14 . McNulty, C. A. M. (1989). Treatment of Campylobacter pylori infection: Microbiological viewpoint. In Campylobacter pylori in Gastritis and Peptic Ulcer Disease (Blaser, M. J., Ed.), pp. 195–207. Igaku-shoin, New York, NY, USA.

15 . Dixon, M. F., Genta, R. M., Yardley, J. H. & Correa, P. (1996). Classification and grading of gastritis. The updated Sydney System. American Journal of Surgical Pathology 20, 1161–81.[ISI][Medline]

16 . Nagata, K., Tsukita, S., Tamura, T. & Sone, N. (1996). A cb-type cytochrome-c oxidase terminates the respiratory chain in Helicobacter pylori. Microbiology 142, 1757–63.[Abstract]

17 . Moss, C. W., Lambert-Fair, M. A., Nicholson, M. A. & Guerrant, G. O. (1990). Isoprenoid quinones of Campylobacter cryaerophilia, C. cinaedi, C. fennelliae, C. hyointestinalis, C. pylori, and ‘C. upsaliensis’. Journal of Clinical Microbiology 28, 395–7.[ISI][Medline]

18 . Tominaga, K., Hamasaki, N., Watanabe, T., Uchida, T., Fujiwara, Y., Takaishi, O. et al. (1999). Effect of culture conditions on morphological changes of Helicobacter pylori. Journal of Gastroenterology 34, Suppl., 28–31.

19 . Nakamura, A., Park, A. M., Nagata, K., Sato, E. F., Kashiba, M., Tamura, T. et al. (2000). Oxidative cellular damage associated with transformation of Helicobacter pylori from a bacillary to a coccoid form. Free Radical Biology and Medicine 28, 1611–8.[ISI][Medline]

20 . Dekker, K. A., Inagaki, T., Gootz, T. D., Huang, L. H., Kojima, Y., Kohlbrenner, W. E. et al. (1998). New quinolone compounds from Pseudonocardia sp. with selective and potent anti-Helicobacter pylori activity: Taxonomy of producing strains, fermentation, isolation, structural eradication and biological activities. Journal of Antibiotics 51, 145–52.[ISI][Medline]

21 . Kunze, B., Hofle, G. & Reichenbach, H. (1987). The aurachins, new quinolone antibiotics from myxobacteria: production, physico-chemical and biological properties. Journal of Antibiotics 40, 258–65.[ISI][Medline]

22 . Drica, K. & Zhao, X. (1997). DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiology and Molecular Biology Reviews 61, 377–92.[Abstract]

23 . Khodursky, A. B. & Cozzarelli, N. R. (1998). The mechanism of inhibition of topoisomerase IV by quinolone antibacterials. Journal of Biological Chemistry 273, 27668–77.[Abstract/Free Full Text]

24 . Nagata, K., Satoh, H., Iwahi, T., Shimoyama, T. & Tamura, T. (1993). Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells. Antimicrobial Agents and Chemotherapy 37, 769–74.[Abstract]

25 . Nakamura, H., Yoshiyama, H., Takeuchi, H., Mizote, T., Okita, K. & Nakazawa, T. (1998). Urease plays an important role in the chemotactic motility of Helicobacter pylori in a viscous environment. Infection and Immunity 66, 4832–7.[Abstract/Free Full Text]

26 . Keto, Y., Takahashi, S. & Okabe, S. (1999). Healing of Helicobacter pylori-induced gastric ulcers in Mongolian gerbils. Digestive Diseases and Sciences 44, 257–65.[ISI][Medline]

27 . Kusuhara, H., Hirayama, F., Matsuyuki, H., Hisadome, M. & Ikeda, Y. (1998). Evaluation of combined antibiotic-omeprazole therapies in Helicobacter pylori-infected Mongolian gerbils. Journal of Gastroenterology 33, 14–7.[ISI][Medline]

28 . Nagata, K., Hirai, K., Koyama, J., Wada, Y. & Tamura, T. (1998). Antimicrobial activity of novel furanonaphthoquinone analogs. Antimicrobial Agents and Chemotherapy 42, 700–2.[Abstract/Free Full Text]

29 . Carbone, M., Fera, M. T., Cecchetti, V., Tabarrini, O., Losi, E., Cusumano, V. et al. (1997). In vitro activities of new quinolones against Helicobacter pylori. Antimicrobial Agents and Chemotherapy 41, 2790–2.[Abstract]

30 . Fung-Tomc, J., Minassian, B., Kolek, B., Washo, T., Huczko, E. & Bonner, D. (2000). In vitro antibacterial spectrum of a new broad-spectrum 8-methoxy fluoroquinone, gatifloxacin. Journal of Antimicrobial Chemotherapy 45, 437–46.[Abstract/Free Full Text]





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