scholarly journals Appearance of a metronidazole-resistant Helicobacter pylori strain in an infected-ICR-mouse model and difference in eradication of metronidazole-resistant and -sensitive strains.

1997 ◽  
Vol 41 (12) ◽  
pp. 2602-2605 ◽  
Author(s):  
S Matsumoto ◽  
Y Washizuka ◽  
Y Matsumoto ◽  
S Tawara ◽  
F Ikeda ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Mouse Model ◽  
Resistant Strain ◽  
Sensitive Strain ◽  
Original Strain ◽  
Antibiotic Resistant ◽  
Icr Mouse ◽  
Resistant Strains ◽  
H Pylori

We tested whether antibiotic-resistant strains appeared in vivo after the failure of treatment using the Helicobacter pylori-infected euthymic mouse model. The numbers of colonies isolated from 56 ICR mice 2 weeks after 4 days of treatment with metronidazole (3.2, 10, or 32 mg/kg of body weight) or amoxicillin (1, 3.2 or 10 mg/kg), with treatment started 4 days after H. pylori CPY2052 inoculation, were counted, and the isolated strains were tested for their sensitivities to two antibiotics to rule out the presence of antibiotic-resistant strains. One metronidazole-resistant strain was detected in a mouse treated with 10 mg of metronidazole per kg, and the MIC of metronidazole for this strain was 25 microg/ml, compared to a MIC of 1.56 microg/ml for the original strain. However, no resistant strain was detected in the amoxicillin treatment group. After the examination described above, mice challenged with a metronidazole-resistant or -sensitive strain isolated from the stomach of a mouse were treated with metronidazole or amoxicillin. The metronidazole-resistant strain was more difficult to eradicate in vivo than the sensitive strain after treatment with metronidazole but not after treatment with amoxicillin. Thus, a metronidazole-resistant H. pylori strain was selected by insufficient treatment, but no resistant strain was selected with amoxicillin. Eradication of a metronidazole-resistant H. pylori strain in vivo required a higher dosage than eradication of a metronidazole-sensitive H. pylori strain. These results may explain one of the reasons for H. pylori treatment failure.

scholarly journals Analysis of rdxA and Involvement of Additional Genes Encoding NAD(P)H Flavin Oxidoreductase (FrxA) and Ferredoxin-Like Protein (FdxB) in Metronidazole Resistance of Helicobacter pylori

2000 ◽  
Vol 44 (8) ◽  
pp. 2133-2142 ◽  
Author(s):  
Dong-Hyeon Kwon ◽  
Fouad A. K. El-Zaatari ◽  
Mototsugu Kato ◽  
Michael S. Osato ◽  
Rita Reddy ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Resistant Strain ◽  
Resistance Mechanisms ◽  
Sensitive Strain ◽  
Metronidazole Resistance ◽  
Genes Encoding ◽  
Resistant Strains ◽  
Flavin Oxidoreductase ◽  
H Pylori

ABSTRACT Metronidazole (Mtz) is a critical ingredient of modern multidrug therapies for Helicobacter pylori infection. Mtz resistance reduces the effectiveness of these combinations. Although null mutations in a rdxA gene that encodes oxygen-insensitive NAD(P)H nitroreductase was reported in Mtz-resistant H. pylori, an intact rdxA gene has also been reported in Mtz-resistant H. pylori, suggesting that additional Mtz resistance mechanisms exist in H. pylori. We explored the nature of Mtz resistance among 544 clinical H. pyloriisolates to clarify the role of rdxA inactivation in Mtz resistance and to identify another gene(s) responsible for Mtz resistance in H. pylori. Mtz resistance was present in 33% (181 of 544) of the clinical isolates. There was marked heterogeneity of resistance, with Mtz MICs ranging from 8 to ≥256 μg/ml.rdxA inactivation resulted in Mtz MICs of up to 32 μg/ml for 6 Mtz-sensitive H. pylori strains and 128 μg/ml for one Mtz-sensitive strain. Single or dual (with rdxA) inactivation of genes that encode ferredoxin-like protein (designatedfdxB) and NAD(P)H flavin oxidoreductase (frxA) also increased the MICs of Mtz for sensitive and resistant strains with low to moderate levels of Mtz resistance. fdxB inactivation resulted in a lower level of resistance than that from rdxAinactivation, whereas frxA inactivation resulted in MICs similar to those seen with rdxA inactivation. Further evidence for involvement of the frxA gene in Mtz resistance included the finding of a naturally inactivated frxA but an intact rdxA in an Mtz-resistant strain, complementation of Mtz sensitivity from an Mtz-sensitive strain to an Mtz-resistant strain or vice versa by use of naturally inactivated or functionalfrxA genes, respectively, and transformation of an Mtz-resistant Escherichia coli strain to an Mtz sensitive strain by a naturally functional frxA gene but not an inactivated frxA gene. These results are consistent with the hypothesis that null mutations in fdxB,frxA, or rdxA may be involved in Mtz resistance.

scholarly journals Efficacy of BB-83698, a Novel Peptide Deformylase Inhibitor, in a Mouse Model of Pneumococcal Pneumonia

2004 ◽  
Vol 48 (1) ◽  
pp. 80-85 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. Mohler ◽  
J. P. Bédos
Keyword(s):  
Mouse Model ◽  
Lung Tissue ◽  
Resistant Strain ◽  
Peptide Deformylase ◽  
In Vitro Activity ◽  
Wild Type ◽  
Virulent Strains ◽  
Resistant Strains

ABSTRACT The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The Streptococcus pneumoniae isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 105 CFU (virulent strains) into immunocompetent mice or 107 CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 μg/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 μg/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 μg · h/ml for plasma and lung tissue, respectively. The emergence of S. pneumoniae isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against S. pneumoniae, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.

scholarly journals Synergistic Therapies as a Promising Option for the Treatment of Antibiotic-Resistant Helicobacter pylori

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 658 ◽  
Author(s):  
Paweł Krzyżek ◽  
Emil Paluch ◽  
Grażyna Gościniak
Keyword(s):  
Helicobacter Pylori ◽  
Antimicrobial Properties ◽  
Multidrug Resistant ◽  
Future Application ◽  
Gastric Diseases ◽  
Antibiotic Resistant ◽  
Minimal Inhibitory Concentrations ◽  
Current Review ◽  
H Pylori

Helicobacter pylori is a Gram-negative bacterium responsible for the development of gastric diseases. The issue of spreading antibiotic resistance of H. pylori and its limited therapeutic options is an important topic in modern gastroenterology. This phenomenon is greatly associated with a very narrow range of antibiotics used in standard therapies and, as a consequence, an alarmingly high detection of multidrug-resistant H. pylori strains. For this reason, scientists are increasingly focused on the search for new substances that will not only exhibit antibacterial effect against H. pylori, but also potentiate the activity of antibiotics. The aim of the current review is to present scientific reports showing newly discovered or repurposed compounds with an ability to enhance the antimicrobial activity of classically used antibiotics against H. pylori. To gain a broader context in their future application in therapies of H. pylori infections, their antimicrobial properties, such as minimal inhibitory concentrations and minimal bactericidal concentrations, dose- and time-dependent mode of action, and, if characterized, anti-biofilm and/or in vivo activity are further described. The authors of this review hope that this article will encourage the scientific community to expand research on the important issue of synergistic therapies in the context of combating H. pylori infections.

scholarly journals Impact of Helicobacter pylori resistance in unsuccessfully pluritreated patients in a Department of Infectious Diseases in Rome

2010 ◽  
Vol 1 (1) ◽  
pp. 3
Author(s):  
Maria Teresa Mascellino ◽  
Barbara Porowska ◽  
Rosa Nicosia ◽  
Alessandra Oliva ◽  
Priscilla Boccia ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Resistance Rate ◽  
Test Method ◽  
Resistance Testing ◽  
Antibiotic Resistant ◽  
Diffusion Technique ◽  
Resistant Strains ◽  
Unrelated Strain ◽  
H Pylori ◽  
Rapid Emergence

Twenty-five pluritreated patients were examined. Fifty-six percent yielded Helicobacter pylori (H. Pilory); of these, 9 patients showed a concomitant colonization of the three gastric regions. The highest resistance rate was found for metronidazole (71.8%) followed by chlaritromycin (53.1%). Amoxycillin showed the best susceptibility (only 6% of resistance), tetracycline showed 12% of resistant strains and levofloxacin appeared to be a promising antibacterial agent (18% of resistance). The E-test method was shown to be more suitable than disk diffusion technique for resistance testing. Combined resistance to both chlaritromycin and metronidazole appeared in 50% of the strains. The isolates showing this dual resistance are known to be difficult to eradicate. Resistotypes were shown to be genotypically different even if the strains with the resistance to both chlaritromycin and metronidazole are more likely to belong to genotype cagA+ and vacA s1m1. Heteroresistance (different susceptibility of the isolated strains in a single stomach) resulted in 36% of patients with pangastritis. Indeed, the concomitant presence of H. pylori strains in the same subject, either susceptible or resistant or vice versa, may interfere with the eradication outcomes. In our study, antibiotic resistant H. pylori typically develops from pre-existing susceptible strains rather than from co-infection with a different and unrelated strain. In fact, each pair of isolates detected in our 4 patients with heteroresistance belonged to the same genotype (cagA+ s1m2 in patient 1 and cagA+ s1m1 in patients 2, 3 and 4). In conclusion, H. pylori antibiotic resistance does present several issues in pluritreated patients owing to the rapid emergence of multi-resistant strains.

scholarly journals Mutations of the Helicobacter pyloriGenes rdxA and pbp1 Cause Resistance against Metronidazole and Amoxicillin

2001 ◽  
Vol 45 (3) ◽  
pp. 962-965 ◽  
Author(s):  
Ralf Paul ◽  
Stefan Postius ◽  
Klaus Melchers ◽  
Klaus P. Schäfer
Keyword(s):  
Helicobacter Pylori ◽  
Resistance Genes ◽  
Resistant Strain ◽  
Parent Strain ◽  
Metronidazole Resistance ◽  
Pcr Products ◽  
Resistant Strains ◽  
H Pylori

ABSTRACT To investigate amoxicillin and metronidazole resistance ofHelicobacter pylori, we compared putative resistance genes between resistant strains obtained in vitro and their sensitive parent strain. All metronidazole-resistant strains hadrdxA mutations, and an amoxicillin-resistant strain hadpbp1 and pbp2 mutations. By transforming PCR products of these mutated genes into antibiotic-sensitive strains, we showed that rdxA null mutations were sufficient for metronidazole resistance, while pbp1mutations contributed to amoxicillin resistance of H. pylori.

scholarly journals Anti-Helicobacter pylori Potential of Artemisinin and Its Derivatives

2012 ◽  
Vol 56 (9) ◽  
pp. 4594-4607 ◽  
Author(s):  
Suchandra Goswami ◽  
Rajendra S. Bhakuni ◽  
Annalakshmi Chinniah ◽  
Anirban Pal ◽  
Sudip K. Kar ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Artemisia Annua ◽  
Infection Model ◽  
Strong Activity ◽  
Content Type ◽  
Content Development ◽  
Candidate Drug ◽  
Resistant Strains ◽  
H Pylori

ABSTRACTThe antimalarial drug artemisinin fromArtemisia annuademonstrated remarkably strong activity againstHelicobacter pylori, the pathogen responsible for peptic ulcer diseases. In an effort to develop a novel antimicrobial chemotherapeutic agent containing such a sesquiterpene lactone endoperoxide, a series of analogues (2 natural and 15 semisynthetic molecules), including eight newly synthesized compounds, were investigated against clinical and standard strains ofH. pylori. The antimicrobial spectrum against 10H. pyloristrains and a few other bacterial and fungal strains indicated specificity against the ulcer causing organism. Of five promising molecules, a newly synthesized ether derivative β-artecyclopropylmether was found to be the most potent compound, which exhibited MIC range, MIC90, and minimum bactericidal concentration range values of 0.25 to 1.0 μg/ml, 1.0 μg/ml, and 1 to 16 μg/ml, respectively, against both resistant and sensitive strains ofH. pylori. The molecule demonstrated strong bactericidal kinetics with extensive morphological degeneration, retained functional efficacy at stomach acidic pH unlike clarithromycin, did not elicit drug resistance unlike metronidazole, and imparted sensitivity to resistant strains. It is not cytotoxic and exhibitsin vivopotentiality to reduce theH. pyloriburden in a chronic infection model. Thus, β-artecyclopropylmether could be a lead candidate for anti-H. pyloritherapeutics. Since the recurrence of gastroduodenal ulcers is believed to be mainly due to antibiotic resistance of the commensal organismH. pylori, development of a candidate drug from this finding is warranted.

scholarly journals Searching for New Tools to Counteract the Helicobacter pylori Resistance: The Positive Action of Resveratrol Derivatives

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 891
Author(s):  
Paola Di Fermo ◽  
Silvia Di Lodovico ◽  
Rosa Amoroso ◽  
Barbara De Filippis ◽  
Simonetta D’Ercole ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Galleria Mellonella ◽  
Soft Agar ◽  
Swarming Motility ◽  
Phenol Derivatives ◽  
Antibiotic Compounds ◽  
Resistant Strains ◽  
H Pylori ◽  
Motility Inhibition

The drug-resistance phenomenon in Helicobacter pylori underlines the need of novel strategies to improve the eradication rate including alternative treatments combining antibiotic and non-antibiotic compounds with synergistic action. In this study, the antibacterial (MIC/MBC) and anti-virulence effects (biofilm reduction and swarming motility inhibition) of resveratrol-RSV and new synthetized RSV-phenol derivatives, with a higher bioavailability, alone and combined with levofloxacin-LVX were evaluated against resistant H. pylori clinical strains. The experiments were confirmed in vivo using the Galleria mellonella model. Among the studied RSV derivatives, RSV-3 and RSV-4 possessed higher antibacterial activity with respect to RSV (MICs from 6.25 to 200 µg/mL and from 3.12 to 200 µg/mL, respectively). RSV, RSV-3, and RSV-4 were able to synergize with LVX restoring its effect in two out of seven clinical resistant strains tested for the study. RSV, RSV-3, and RSV-4, alone and with LVX at sub-MIC and sub-synergistic concentrations, significantly reduced the biofilm formation. Moreover, RSV-3 and RSV-4 reduced the H. pylori swarming motility on soft agar. RSV, RSV-3, and RSV-4 were non-toxic for G. mellonella larvae and displayed a protective effect against H. pylori infection. Overall, RSV–phenol derivatives should be considered interesting candidates for innovative therapeutic schemes to tackle the H. pylori antibiotic resistance.

scholarly journals In VitroandIn VivoActivities of HPi1, a Selective Antimicrobial against Helicobacter pylori

2014 ◽  
Vol 58 (6) ◽  
pp. 3255-3260 ◽  
Author(s):  
Ekaterina Gavrish ◽  
Binu Shrestha ◽  
Chao Chen ◽  
Ida Lister ◽  
E. Jeffrey North ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Mouse Model ◽  
Susceptibility Testing ◽  
Limit Of Detection ◽  
Time Dependent ◽  
Content Type ◽  
Commercial Sources ◽  
H Pylori

ABSTRACTA high-throughput screen (HTS) was performed to identify molecules specifically active againstHelicobacter pylori, the causative agent of peptic ulcer and gastric carcinoma. Currently, treatment ofH. pyloriinfection is suboptimal, with failure rates approaching 25%, despite triple therapy with two broad-spectrum antibiotics and a proton pump inhibitor or quadruple therapy with added bismuth. The HTS was performed in 384-well plates, and reduction of the metabolic indicator resazurin was used as a reporter for cell growth. Diverse molecules from commercial sources were identified as hits, andin vitrovalidations included measurements of MIC and time-dependent killing as well as anaerobic susceptibility testing against a panel of gut microbes.In vivovalidation included testing in the mouse model ofH. pyloriinfection. The small molecule HPi1 (3-hydrazinoquinoxaline-2-thiol) had excellent potency, with an MIC of 0.08 to 0.16 μg/ml and good selectivity forH. pyloricompared to a panel of commensal bacteria. HPi1 was also effective in a mouse model ofH. pyloriinfection, reducing colony counts to below the limit of detection after oral dosing of 25 mg/kg/day for 3 days. HPi1 is a promising lead in the search for more effective and specificH. pyloritherapeutics.

scholarly journals Cholestenone functions as an antibiotic against Helicobacter pylori by inhibiting biosynthesis of the cell wall component CGL

2021 ◽  
Vol 118 (16) ◽  
pp. e2016469118
Author(s):  
Junichi Kobayashi ◽  
Masatomo Kawakubo ◽  
Chifumi Fujii ◽  
Nobuhiko Arisaka ◽  
Masaki Miyashita ◽  
...  
Keyword(s):  
Cell Wall ◽  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Control Diet ◽  
Inhibitory Effects ◽  
Oral Medicine ◽  
Resistant Strains ◽  
H Pylori

Helicobacter pylori, a pathogen responsible for gastric cancer, contains a unique glycolipid, cholesteryl-α-D-glucopyranoside (CGL), in its cell wall. Moreover, O-glycans having α1,4-linked N-acetylglucosamine residues (αGlcNAc) are secreted from gland mucous cells of gastric mucosa. Previously, we demonstrated that CGL is critical for H. pylori survival and that αGlcNAc serves as antibiotic against H. pylori by inhibiting CGL biosynthesis. In this study, we tested whether a cholesterol analog, cholest-4-en 3-one (cholestenone), exhibits antibacterial activity against H. pylori in vitro and in vivo. When the H. pylori standard strain ATCC 43504 was cultured in the presence of cholestenone, microbial growth was significantly suppressed dose-dependently relative to microbes cultured with cholesterol, and cholestenone inhibitory effects were not altered by the presence of cholesterol. Morphologically, cholestenone-treated H. pylori exhibited coccoid forms. We obtained comparable results when we examined the clarithromycin-resistant H. pylori strain “2460.” We also show that biosynthesis of CGL and its derivatives cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside and cholesteryl-6-O-phosphatidyl-α-D-glucopyranoside in H. pylori is remarkably inhibited in cultures containing cholestenone. Lastly, we asked whether orally administered cholestenone eradicated H. pylori strain SS1 in C57BL/6 mice. Strikingly, mice fed a cholestenone-containing diet showed significant eradication of H. pylori from the gastric mucosa compared with mice fed a control diet. These results overall strongly suggest that cholestenone could serve as an oral medicine to treat patients infected with H. pylori, including antimicrobial-resistant strains.

scholarly journals Exposure to Metronidazole In Vivo Readily Induces Resistance in Helicobacter pylori and Reduces the Efficacy of Eradication Therapy in Mice

1999 ◽  
Vol 43 (4) ◽  
pp. 777-781 ◽  
Author(s):  
Peter J. Jenks ◽  
Agnes Labigne ◽  
Richard L. Ferrero
Keyword(s):  
Helicobacter Pylori ◽  
Eradication Therapy ◽  
Resistance Mechanisms ◽  
Prior Exposure ◽  
Separate Experiment ◽  
Suitable Model ◽  
Resistant Strains ◽  
Mixed Populations ◽  
H Pylori

ABSTRACT The Helicobacter pylori SS1 mouse model was used to characterize the development of resistance in H. pyloriafter treatment with metronidazole monotherapy and to examine the effect of prior exposure to metronidazole on the efficacy of a metronidazole-containing eradication regimen. Mice colonized with the metronidazole-sensitive H. pyloriSS1 strain were treated for 7 days with either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole once a day or three times per day (TID). In a separate experiment,H. pylori-infected mice were administered either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole TID for 7 days, followed 1 month later by either peptone trypsin broth or the mouse equivalent of 20 mg of omeprazole, 250 mg of clarithromycin, and 400 mg of metronidazole twice a day for 7 days. At least 1 month after the completion of treatment, the mice were sacrificed and their stomachs were cultured for H. pylori. The susceptibilities of isolates to metronidazole were assessed by agar dilution determination of the MICs. Mixed populations of metronidazole-resistant and -sensitive strains were isolated from 70% of mice treated with 400 mg of metronidazole TID. The ratio of resistant to sensitive strains was 1:100, and the MICs for the resistant strains varied from 8 to 64 μg/ml. In the second experiment, H. pylori was eradicated from 70% of mice treated with eradication therapy alone, compared to 25% of mice pretreated with metronidazole (P < 0.01). Mice still infected after treatment with metronidazole and eradication therapy contained mixed populations of metronidazole-resistant and -sensitive isolates in a ratio of 1:25. These results demonstrate thatH. pylori readily acquires resistance to metronidazole in vivo and that prior exposure of the organism to metronidazole is associated with failure of eradication therapy. H. pylori-infected mice provide a suitable model for the study of resistance mechanisms inH. pylori and will be useful in determining optimal regimens for the eradication of resistant strains.

Sign in / Sign up

Export Citation Format

Share Document