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 Role of Energy Sensor TlpD of Helicobacter pylori in Gerbil Colonization and Genome Analyses after Adaptation in the Gerbil

2013 ◽  
Vol 81 (10) ◽  
pp. 3534-3551 ◽  
Author(s):  
Wiebke Behrens ◽  
Tobias Schweinitzer ◽  
Joena Bal ◽  
Martina Dorsch ◽  
André Bleich ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Human Isolate ◽  
Infection Model ◽  
Energy Yield ◽  
Content Type ◽  
Full Characterization ◽  
H Pylori ◽  
The Impact

ABSTRACTHelicobacter pylorimaintains colonization in its human host using a limited set of taxis sensors. TlpD is a proposed energy taxis sensor ofH. pyloriand dominant under environmental conditions of low bacterial energy yield. We studied the impact ofH. pyloriTlpD on colonizationin vivousing a gerbil infection model which closely mimics the gastric physiology of humans. A gerbil-adaptedH. pyloristrain, HP87 P7, showed energy-dependent behavior, while its isogenictlpDmutant lost it. A TlpD-complemented strain regained the wild-type phenotype. Infection of gerbils with the complemented strain demonstrated that TlpD is important for persistent infection in the antrum and corpus and suggested a role of TlpD in horizontal navigation and persistent corpus colonization. As a part of the full characterization of the model and to gain insight into the genetic basis ofH. pyloriadaptation to the gerbil, we determined the complete genome sequences of the gerbil-adapted strain HP87 P7, two HP87 P7tlpDmutants before and after gerbil passage, and the original human isolate, HP87. The integrity of the genome, including that of a functionalcagpathogenicity island, was maintained after gerbil adaptation. Genetic and phenotypic differences between the strains were observed. Major differences between the gerbil-adapted strain and the human isolate emerged, including evidence of recent recombination. Passage of thetlpDmutant through the gerbil selected for gain-of-function variation in a fucosyltransferase gene,futC(HP0093). In conclusion, a gerbil-adaptedH. pyloristrain with a stable genome has helped to establish that TlpD has important functions for persistent colonization in the stomach.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

scholarly journals Development of a Tetracycline-Inducible Gene Expression System for the Study of Helicobacter pylori Pathogenesis

2013 ◽  
Vol 79 (23) ◽  
pp. 7351-7359 ◽  
Author(s):  
Aleksandra W. Debowski ◽  
Phebe Verbrugghe ◽  
Miriam Sehnal ◽  
Barry James Marshall ◽  
Mohammed Benghezal
Keyword(s):  
Helicobacter Pylori ◽  
Animal Models ◽  
Chronic Infection ◽  
Fluorescent Protein ◽  
Expression System ◽  
Content Type ◽  
Conditional Expression ◽  
H Pylori ◽  
Green Fluorescent

ABSTRACTDeletion mutants and animal models have been instrumental in the study ofHelicobacter pyloripathogenesis. Conditional mutants, however, would enable the study of the temporal gene requirement duringH. pyloricolonization and chronic infection. To achieve this goal, we adapted theEscherichia coliTn10-derived tetracycline-inducible expression system for use inH. pylori. TheureApromoter was modified by inserting one or twotetoperators to generate tetracycline-responsive promoters, nameduPtetO, and these promoters were then fused to the reportergfpmut2 and inserted into different loci. The expression of the tetracycline repressor (tetR) was placed under the control of one of three promoters and inserted into the chromosome. Conditional expression of green fluorescent protein (GFP) in strains harboringtetRanduPtetO-GFPwas characterized by measuring GFP activity and by immunoblotting. The twotet-responsiveuPtetOpromoters differ in strength, and induction of these promoters was inducer concentration and time dependent, with maximum expression achieved after induction for 8 to 16 h. Furthermore, the chromosomal location of theuPtetO-GFPconstruct and the nature of the promoter driving expression oftetRinfluenced the strength of theuPtetOpromoters upon induction. Integration ofuPtetO-GFPandtetRconstructs at different genomic loci was stablein vivoand did not affect colonization. Finally, we demonstrate tetracycline-dependent induction of GFP expressionin vivoduring chronic infection. These results open new experimental avenues for dissectingH. pyloripathogenesis using animal models and for testing the roles of specific genes in colonization of, adaptation to, and persistence in the host.

scholarly journals Cholesterol Enhances Helicobacter pylori Resistance to Antibiotics and LL-37

2011 ◽  
Vol 55 (6) ◽  
pp. 2897-2904 ◽  
Author(s):  
David J. McGee ◽  
Alika E. George ◽  
Elizabeth A. Trainor ◽  
Katherine E. Horton ◽  
Ellen Hildebrandt ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Lipid A ◽  
Polymyxin B ◽  
Defined Medium ◽  
Vital Role ◽  
Content Type ◽  
The Two Cultures ◽  
H Pylori ◽  
The Impact

ABSTRACTThe human gastric pathogenHelicobacter pyloristeals host cholesterol, modifies it by glycosylation, and incorporates the glycosylated cholesterol onto its surface via a cholesterol glucosyltransferase, encoded bycgt. The impact of cholesterol onH. pyloriantimicrobial resistance is unknown.H. pyloristrain 26695 was cultured in Ham's F12 chemically defined medium in the presence or absence of cholesterol. The two cultures were subjected to overnight incubations with serial 2-fold dilutions of 12 antibiotics, six antifungals, and seven antimicrobial peptides (including LL-37 cathelicidin and human alpha and beta defensins). Of 25 agents tested, cholesterol-grownH. pyloricells were substantially more resistant (over 100-fold) to nine agents than wereH. pyloricells grown without cholesterol. These nine agents included eight antibiotics and LL-37.H. pyloriwas susceptible to the antifungal drug pimaricin regardless of cholesterol presence in the culture medium. Acgtmutant retained cholesterol-dependent resistance to most antimicrobials but displayed increased susceptibility to colistin, suggesting an involvement of lipid A. Mutation oflpxE, encoding lipid A1-phosphatase, led to loss of cholesterol-dependent resistance to polymyxin B and colistin but not other antimicrobials tested. Thecgtmutant was severely attenuated in gerbils, indicating that glycosylation is essentialin vivo. These findings suggest that cholesterol plays a vital role in virulence and contributes to the intrinsic antibiotic resistance ofH. pylori.

scholarly journals In Vitro and In Vivo Antibacterial Activities of Patchouli Alcohol, a Naturally Occurring Tricyclic Sesquiterpene, against Helicobacter pylori Infection

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Y. F. Xu ◽  
D. W. Lian ◽  
Y. Q. Chen ◽  
Y. F. Cai ◽  
Y. F. Zheng ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Bacterial Resistance ◽  
Clinical Isolates ◽  
Potential Candidate ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Patchouli Alcohol ◽  
H Pylori

ABSTRACT This study further evaluated the in vitro and in vivo anti-Helicobacter pylori activities and potential underlying mechanism of patchouli alcohol (PA), a tricyclic sesquiterpene. In the in vitro assay, the capacities of PA to inhibit and kill H. pylori were tested on three standard strains at different pH values and on 12 clinical isolates. The effects of PA on H. pylori adhesion (and its alpA, alpB, and babA genes), motility (and its flaA and flaB genes), ultrastructure, and flagellation were investigated. Moreover, the H. pylori resistance to and postantibiotic effect (PAE) of PA were determined. Furthermore, the in vivo effects of PA on H. pylori eradication and gastritis were examined. Results showed that MICs of PA against three standard strains (pH 5.3 to 9) and 12 clinical isolates were 25 to 75 and 12.5 to 50 μg/ml, respectively. The killing kinetics of PA were time and concentration dependent, and its minimal bactericidal concentrations (MBCs) were 25 to 75 μg/ml. In addition, H. pylori adhesion, motility, ultrastructure, and flagellation were significantly suppressed. PA also remarkably inhibited the expression of adhesion genes (alpA and alpB) and motility genes (flaA and flaB). Furthermore, PA treatment caused a longer PAE and less bacterial resistance than clarithromycin and metronidazole. The in vivo study showed that PA can effectively eradicate H. pylori, inhibit gastritis, and suppress the expression of inflammatory mediators (COX-2, interleukin 1β, tumor necrosis factor alpha, and inducible nitric oxide synthase [iNOS]). In conclusion, PA can efficiently kill H. pylori, interfere with its infection process, and attenuate gastritis with less bacterial resistance, making it a potential candidate for new drug development.

scholarly journals Helicobacter pylori Stores Nickel To Aid Its Host Colonization

2012 ◽  
Vol 81 (2) ◽  
pp. 580-584 ◽  
Author(s):  
Stéphane L. Benoit ◽  
Erica F. Miller ◽  
Robert J. Maier
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Physiological Role ◽  
Wild Type ◽  
Rank Tests ◽  
Content Type ◽  
Host Mouse ◽  
H Pylori ◽  
Very High

ABSTRACTThe transition metal nickel (Ni) is critical for the pathogenicity ofHelicobacter pylori. Indeed the element is a required component of two enzymes, hydrogenase and urease, that have been shown to be important forin vivocolonization of the host gastric mucosa. Urease accounts for up to 10% of the total cellularH. pyloriprotein content, and therefore the bacterial Ni demand is very high.H. pyloripossess two small and abundant histidine-rich, Ni-binding proteins, Hpn and Hpn-like, whose physiological role in the host have not been investigated. In this study, special husbandry conditions were used to control Ni levels in the host (mouse), including the use of Ni-free versus Ni-supplemented food. The efficacy of each diet was confirmed by measuring the Ni concentrations in sera of mice fed with either diet. Colonization levels (based on rank tests) of theΔhpn Δhpn-like double mutants isolated from the mice provided Ni-deficient chow were statistically lower than those for mice given Ni in their diet. In contrast,H. pyloriwild-type colonization levels were similar in both host groups (e.g., regardless of Ni levels). Our results indicate that the gastric pathogenH. pylorican utilize stored Ni via defined histidine-rich proteins to aid colonization of the host.

scholarly journals Efficacy of Daptomycin-Cloxacillin Combination in Experimental Foreign-Body Infection Due to Methicillin-Resistant Staphylococcus aureus

2012 ◽  
Vol 56 (7) ◽  
pp. 3806-3811 ◽  
Author(s):  
C. Garrigós ◽  
O. Murillo ◽  
J. Lora-Tamayo ◽  
R. Verdaguer ◽  
F. Tubau ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Foreign Body ◽  
Infection Model ◽  
Cure Rate ◽  
Methicillin Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
High Doses ◽  
Rat Tissue

ABSTRACTDespite the use of daptomycin alone at high doses (greater than 6 mg/kg of body weight/day) against difficult-to-treat infections, clinical failures and resistance appeared. Recently, the combination daptomycin-cloxacillin showed enhanced efficacy in clearing bacteremia caused by methicillin-resistantStaphylococcus aureus(MRSA). The aim of this study was to evaluate the efficacy of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg/day in humans, respectively) in combination with cloxacillin in a rat tissue cage infection model by MRSA and to compare its efficacy to that of daptomycin-rifampin. We used MRSA strain ATCC BAA-39. In the log- and stationary-phase kill curves, daptomycin-cloxacillin improved the bactericidal activity of daptomycin, especially in log phase. Forin vivostudies, therapy was administered intraperitoneally for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day (daptomycin 100 and daptomycin 45), daptomycin 100-cloxacillin at 200 mg/kg/12 h, daptomycin 45-cloxacillin, and daptomycin 100-rifampin at 25 mg/kg/12 h. Daptomycin-rifampin was the best therapy (P< 0.05). Daptomycin 45 was the least effective treatment and did not protect against the emergence of resistant strains. There were no differences between the two dosages of daptomycin plus cloxacillin in any situation, and both protected against resistance. The overall effect of the addition of cloxacillin to daptomycin was a significantly greater cure rate (against adhered bacteria) than that for daptomycin alone. In conclusion, daptomycin-cloxacillin enhanced modestly thein vivoefficacy of daptomycin alone against foreign-body infection by MRSA and was less effective than daptomycin plus rifampin. The benefits of adding cloxacillin to daptomycin should be especially evaluated against infections by rifampin-resistant MRSA and for protection against the emergence of daptomycin nonsusceptibility.

scholarly journals Pyridodiazepine Amines Are Selective Therapeutic Agents for Helicobacter pylori by Suppressing Growth through Inhibition of Glutamate Racemase but Are Predicted To Require Continuous Elevated Levels in Plasma To Achieve Clinical Efficacy

2015 ◽  
Vol 59 (4) ◽  
pp. 2337-2342 ◽  
Author(s):  
Boudewijn L. M. de Jonge ◽  
Amy Kutschke ◽  
Joseph V. Newman ◽  
Michael T. Rooney ◽  
Wei Yang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Therapeutic Agents ◽  
Infection Model ◽  
Content Type ◽  
Peptidoglycan Biosynthesis ◽  
Glutamate Racemase ◽  
Mouse Infection Model ◽  
Exposure Levels ◽  
H Pylori ◽  
Extended Exposure

ABSTRACTA pyridodiazepine amine inhibitor ofHelicobacter pyloriglutamate racemase (MurI) was characterized. The compound was selectively active againstH. pylori, and growth suppression was shown to be mediated through the inhibition of MurI by several methods. In killing kinetics experiments, the compound showed concentration-independent activity, with about a 2-log loss of viability in 24 h. A demonstration of efficacy in a mouse infection model was attempted but not achieved, and this was attributed to the failure to attain extended exposure levels above the MIC for >95% of the time. This index and magnitude were derived from pharmacokinetic-pharmacodynamic (PK-PD) studies with amoxicillin, another inhibitor of peptidoglycan biosynthesis that showed slow killing kinetics similar to those of the pyridodiazepine amines. These studies indicate that MurI and other enzymes involved in peptidoglycan biosynthesis may be less desirable targets for monotherapy directed againstH. pyloriif once-a-day dosing is required.

scholarly journals A Comparison of Murine and Human Immunoproteomes of Helicobacter pylori Validates the Preclinical Murine Infection Model for Antigen Screening

2002 ◽  
Vol 70 (11) ◽  
pp. 6494-6498 ◽  
Author(s):  
Dirk Bumann ◽  
Petra Holland ◽  
Frank Siejak ◽  
Jan Koesling ◽  
Nicolas Sabarth ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Vaccine Development ◽  
Protein Composition ◽  
Infection Model ◽  
Host Immune System ◽  
High Agreement ◽  
Infection Models ◽  
H Pylori ◽  
Human Infections

ABSTRACT Preclinical mouse infection models are widely used for Helicobacter vaccine development, but how well such models mimic important aspects of human infections is unknown. A comparison of Helicobacter pylori immunoproteomes of infected mice with previously reported patient data reveals a high agreement in the antigens recognized, suggesting that H. pylori in vivo protein composition and recognition by the host immune system are comparable in mice and humans. Murine Helicobacter models may thus be valid to screen antigens for human vaccination.

scholarly journals Hydrogen Peroxide-Mediated Oxygen Enrichment Eradicates Helicobacter pylori In Vitro and In Vivo

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Jia Di ◽  
Jun Zhang ◽  
Lei Cao ◽  
Ting-ting Huang ◽  
Jun-xia Zhang ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Helicobacter Pylori ◽  
Bacterial Cell ◽  
Cell Membranes ◽  
Enriched Environment ◽  
Mongolian Gerbils ◽  
Content Type ◽  
H Pylori

ABSTRACT Helicobacter pylori is an important risk factor for gastric ulcers. However, antibacterial therapies increase the resistance rate and decrease the eradication rate of H. pylori. Inspired by the microaerophilic characteristics of H. pylori, we aimed at effectively establishing an oxygen-enriched environment to eradicate and prevent the recurrence of H. pylori. The effect and the mechanism of an oxygen-enriched environment in eradicating H. pylori and preventing the recurrence were explored in vitro and in vivo. During oral administration and after drug withdrawal, H. pylori counts were evaluated by Giemsa staining in animal cohorts. An oxygen-enriched environment in which H. pylori could not survive was successfully established by adding hydrogen peroxide into several solutions and rabbit gastric juice. Hydrogen peroxide effectively killed H. pylori in Columbia blood agar and special peptone broth. Minimum inhibition concentrations and minimum bactericidal concentrations of hydrogen peroxide were both relatively stable after promotion of resistance for 30 generations, indicating that hydrogen peroxide did not easily promote resistance in H. pylori. In models of Mongolian gerbils and Kunming mice, hydrogen peroxide has been shown to significantly eradicate and effectively prevent the recurrence of H. pylori without toxicity and damage to the gastric mucosa. The mechanism of hydrogen peroxide causing H. pylori death was related to the disruption of bacterial cell membranes. The oxygen-enriched environment achieved by hydrogen peroxide eradicates and prevents the recurrence of H. pylori by damaging bacterial cell membranes. Hydrogen peroxide thus provides an attractive candidate for anti-H. pylori treatment.

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