scholarly journals Identification of novel bacterial urease inhibitors through molecular shape and structure based virtual screening approaches

RSC Advances ◽  
2020 ◽  
Vol 10 (27) ◽  
pp. 16061-16070
Author(s):  
Muhammad Imran ◽  
Saba Waqar ◽  
Koji Ogata ◽  
Mahmood Ahmed ◽  
Zobia Noreen ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Virtual Screening ◽  
Acid Resistance ◽  
Molecular Shape ◽  
Urease Inhibitors ◽  
H Pylori ◽  
Screening Approaches

The enzyme urease is an essential colonizing factor of the notorious carcinogenic pathogen Helicobacter pylori (H. pylori), conferring acid resistance to the bacterium.

scholarly journals The Orphan Response Regulator HP1021 of Helicobacter pylori Regulates Transcription of a Gene Cluster Presumably Involved in Acetone Metabolism

2007 ◽  
Vol 189 (6) ◽  
pp. 2339-2349 ◽  
Author(s):  
Michael Pflock ◽  
Melanie Bathon ◽  
Jennifer Schär ◽  
Stefanie Müller ◽  
Hans Mollenkopf ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gene Cluster ◽  
Response Regulator ◽  
Transcriptional Profiling ◽  
Acid Resistance ◽  
Housekeeping Genes ◽  
Open Reading Frames ◽  
Considerable Impact ◽  
Two Component Systems ◽  
H Pylori

ABSTRACT Helicobacter pylori is a gastric pathogen for which no nonhuman reservoir is known. In accordance with the tight adaptation to its unique habitat, the human stomach, H. pylori is endowed with a very restricted repertoire of regulatory proteins. Nevertheless, the three complete two-component systems of H. pylori were shown to be involved in the regulation of important virulence traits like motility and acid resistance and in the control of metal homeostasis. HP1021 is an orphan response regulator with an atypical receiver domain whose inactivation has a considerable impact on the growth of H. pylori. Here we report the identification of HP1021-regulated genes by whole-genome transcriptional profiling. We show that the transcription of the essential housekeeping genes nifS and nifU, which are required for the assembly of Fe-S clusters, is activated by HP1021. Furthermore, we demonstrate that the expression of a gene cluster comprising open reading frames hp0690 to hp0693 and hp0695 to hp0697 which is probably involved in acetone metabolism is strongly upregulated by HP1021. Evidence is provided for a direct regulation of the hp0695-to-hp0697 operon by the binding of HP1021 to its promoter region.

scholarly journals Helicobacter pylori Containing Only Cytoplasmic Urease Is Susceptible to Acid

1998 ◽  
Vol 66 (11) ◽  
pp. 5060-5066 ◽  
Author(s):  
Partha Krishnamurthy ◽  
Mary Parlow ◽  
Jason B. Zitzer ◽  
Nimish B. Vakil ◽  
Harry L. T. Mobley ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Urease Activity ◽  
Acid Resistance ◽  
Etiologic Agent ◽  
Stationary Phase Culture ◽  
Colonization Factor ◽  
Acid Environment ◽  
H Pylori

ABSTRACT Helicobacter pylori, an important etiologic agent in a variety of gastroduodenal diseases, produces large amounts of urease as an essential colonization factor. We have demonstrated previously that urease is located within the cytoplasm and on the surface of H. pylori both in vivo and in stationary-phase culture. The purpose of the present study was to assess the relative contributions of cytoplasmic and surface-localized urease to the ability of H. pylori to survive exposure to acid in the presence of urea. Toward this end, we compared the acid resistance in vitro of H. pylori cells which possessed only cytoplasmic urease to that of bacteria which possessed both cytoplasmic and surface-localized or extracellular urease. Bacteria with only cytoplasmic urease activity were generated by using freshly subcultured bacteria or by treating repeatedly subcultured H. pylori with flurofamide (1 μM), a potent, but poorly diffusible urease inhibitor. H. pyloriwith cytoplasmic and surface-located urease activity survived in an acid environment when 5 mM urea was present. In contrast, H. pylori with only cytoplasmic urease shows significantly reduced survival when exposed to acid in the presence of 5 mM urea. Similarly,Escherichia coli SE5000 expressing H. pyloriurease and the Ni2+ transport protein NixA, which expresses cytoplasmic urease activity at levels similar to those in wild-typeH. pylori, survived minimally when exposed to acid in the presence of 5 to 50 mM urea. We conclude that cytoplasmic urease activity alone is not sufficient (although cytoplasmic urease activity is likely to be necessary) to allow survival of H. pyloriin acid; the activity of surface-localized urease is essential for resistance of H. pylori to acid under the assay conditions used. Therefore, the mechanism whereby urease becomes associated with the surface of H. pylori, which involves release of the enzyme from bacteria due to autolysis followed by adsorption of the enzyme to the surface of intact bacteria (“altruistic autolysis”), is essential for survival of H. pylori in an acid environment. The ability of H. pylori to survive exposure to low pH is likely to depend on a combination of both cytoplasmic and surface-associated urease activities.

scholarly journals The Helicobacter pylori Homologue of the Ferric Uptake Regulator Is Involved in Acid Resistance

2002 ◽  
Vol 70 (2) ◽  
pp. 606-611 ◽  
Author(s):  
Jetta J. E. Bijlsma ◽  
Barbara Waidner ◽  
Arnoud H. M. van Vliet ◽  
Nicky J. Hughes ◽  
Stephanie Häg ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Acid Resistance ◽  
Low Ph ◽  
Main Function ◽  
Ferric Uptake Regulator ◽  
Acidic Ph ◽  
Human Pathogen ◽  
H Pylori

ABSTRACT The only known niche of the human pathogen Helicobacter pylori is the gastric mucosa, where large fluctuations of pH occur, indicating that the bacterial response and resistance to acid are important for successful colonization. One of the few regulatory proteins in the H. pylori genome is a homologue of the ferric uptake regulator (Fur). In most bacteria, the main function of Fur is the regulation of iron homeostasis. However, in Salmonella enterica serovar Typhimurium, Fur also plays an important role in acid resistance. In this study, we determined the role of the H. pylori Fur homologue in acid resistance. Isogenic fur mutants were generated in three H. pylori strains (1061, 26695, and NCTC 11638). At pH 7 there was no difference between the growth rates of mutants and the parent strains. Under acidic conditions, growth of the fur mutants was severely impaired. No differences were observed between the survival of the fur mutant and parent strain 1061 after acid shock. Addition of extra iron or removal of iron from the growth medium did not improve the growth of the fur mutant at acidic pH. This indicates that the phenotype of the fur mutant at low pH was not due to increased iron sensitivity. Transcription of fur was repressed in response to low pH. From this we conclude that Fur is involved in the growth at acidic pH of H. pylori; as such, it is the first regulatory protein implicated in the acid resistance of this important human pathogen.

scholarly journals Medium pH-dependent redistribution of the urease of Helicobacter pylori

2003 ◽  
Vol 52 (3) ◽  
pp. 211-216 ◽  
Author(s):  
Wu Hong ◽  
Kouichi Sano ◽  
Shinichi Morimatsu ◽  
David R. Scott ◽  
David L. Weeks ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Intracellular Transport ◽  
Acid Resistance ◽  
Gastric Disease ◽  
Acidic Ph ◽  
Gold Particles ◽  
Outer Portion ◽  
H Pylori ◽  
Extracellular Environment

Helicobacter pylori is an aetiological agent of gastric disease. Although the role of urease in gastric colonization of H. pylori has been shown, it remains unclear as to where urease is located in this bacterial cell. The purpose of this study was to define the urease-associated apparatus in the H. pylori cytoplasm. H. pylori was incubated at both a neutral and an acidic pH in the presence or absence of urea and examined by double indirect immunoelectron microscopy. The density of gold particles for UreA was greatest in the inner portion of the wild-type H. pylori cytoplasm at neutral pH but was greatest in the outer portion at acidic pH. This difference was independent of the presence of urea and was not observed in the ureI-deletion mutant. Also, the eccentric shift of urease in acidic pH was not observed in UreI. After a 2 day incubation period at acidic pH, it was observed that the urease gold particles in H. pylori assembled and were associated with UreI gold particles. Urease immunoreactivity shifted from the inner to the outer portion of H. pylori as a result of an extracellular decrease in pH. This shift was urea-independent and UreI-dependent, suggesting an additional role of UreI in urease-dependent acid resistance. This is the first report of the intracellular transport of molecules in bacteria in response to changes in the extracellular environment.

scholarly journals Characterization of the ArsRS Regulon of Helicobacter pylori, Involved in Acid Adaptation

2006 ◽  
Vol 188 (10) ◽  
pp. 3449-3462 ◽  
Author(s):  
Michael Pflock ◽  
Nadja Finsterer ◽  
Biju Joseph ◽  
Hans Mollenkopf ◽  
Thomas F. Meyer ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Response Regulator ◽  
Transcriptional Profiling ◽  
Acid Resistance ◽  
Two Component System ◽  
Gene Encoding ◽  
Acid Adaptation ◽  
Genes Encoding ◽  
H Pylori ◽  
A Site

ABSTRACT The human gastric pathogen Helicobacter pylori is extremely well adapted to the highly acidic conditions encountered in the stomach. The pronounced acid resistance of H. pylori relies mainly on the ammonia-producing enzyme urease; however, urease-independent mechanisms are likely to contribute to acid adaptation. Acid-responsive gene regulation is mediated at least in part by the ArsRS two-component system consisting of the essential OmpR-like response regulator ArsR and the nonessential cognate histidine kinase ArsS, whose autophosphorylation is triggered in response to low pH. In this study, by global transcriptional profiling of an ArsS-deficient H. pylori mutant grown at pH 5.0, we define the ArsR∼P-dependent regulon consisting of 109 genes, including the urease gene cluster, the genes encoding the aliphatic amidases AmiE and AmiF, and the rocF gene encoding arginase. We show that ArsR∼P controls the acid-induced transcription of amiE and amiF by binding to extended regions located upstream of the −10 box of the respective promoters. In contrast, transcription of rocF is repressed by ArsR∼P at neutral, acidic, and mildly alkaline pH via high-affinity binding of the response regulator to a site overlapping the promoter of the rocF gene.

scholarly journals Requirement of Histidine Kinases HP0165 and HP1364 for Acid Resistance in Helicobacter pylori

2006 ◽  
Vol 74 (5) ◽  
pp. 3052-3059 ◽  
Author(s):  
John T. Loh ◽  
Timothy L. Cover
Keyword(s):  
Helicobacter Pylori ◽  
Type Strain ◽  
Wild Type Strain ◽  
Acid Resistance ◽  
Wild Type ◽  
Histidine Kinases ◽  
Mutant Strains ◽  
Two Component Signal Transduction ◽  
Reporter Assays ◽  
H Pylori

ABSTRACT In this study, we investigated a potential requirement of two-component signal transduction systems for acid resistance in Helicobacter pylori. In comparison to a wild-type strain, isogenic strains with null mutations in either HP0165 or HP1364 histidine kinases were impaired in their ability to grow at pH 5.0. The growth of complemented mutant strains was similar to that of the wild-type strain. H. pylori DNA array analyses and transcriptional reporter assays indicated that acid-responsive gene transcription was altered in the HP0165 and HP1364 null mutant strains compared to the parental wild-type strain. These results indicate that intact HP0165 and HP1364 histidine kinases are required for acid resistance in H. pylori.

scholarly journals Clinical Relevance of Helicobacter pylori Infection

2021 ◽  
Vol 10 (16) ◽  
pp. 3473
Author(s):  
Irena Mladenova
Keyword(s):  
Helicobacter Pylori ◽  
Age Groups ◽  
Acid Resistance ◽  
Clinical Indication ◽  
Clinical Aspects ◽  
Gastric Disease ◽  
Upper Gastrointestinal Endoscopy ◽  
World Population ◽  
Ulcer Disease ◽  
H Pylori

Helicobacter pylori (H. pylori) is a Gram-negative helical, microaerophilic bacterium which colonizes the antrum and body of the stomach, surviving in its harsh environment through mechanisms of acid resistance and colonization factors. It infects approximately 50% of the world population. Although the prevalence of this infection varies from country to country, as well as between different ethnic, social or age groups, it is estimated that about 50% of the human population only carries this microorganism. While H. pylori has been found to play a major etiological and pathogenic role in chronic gastritis, peptic ulcer disease and gastric cancer, its importance for many types of extra-gastric disease needs to be further investigated. The choice of tests to diagnose H. pylori infection, defined as invasive or non-invasive, depends on the clinical indication as to whether to perform upper gastrointestinal endoscopy. Focusing on bacterial eradication, the treatment should be decided locally based on the use of antibiotics and documented antibiotic resistance. The author provides an overview of the current state of knowledge about the clinical aspects of H. pylori infection, especially its diagnostic and therapeutic management.

scholarly journals Differential regulation of urease activity in Helicobacter hepaticus and Helicobacter pylori

Microbiology ◽  
2005 ◽  
Vol 151 (12) ◽  
pp. 3989-3995 ◽  
Author(s):  
Clara Belzer ◽  
Jeroen Stoof ◽  
Catherine S. Beckwith ◽  
Ernst J. Kuipers ◽  
Johannes G. Kusters ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Urease Activity ◽  
Inflammatory Diseases ◽  
Acid Resistance ◽  
Maximum Level ◽  
Helicobacter Hepaticus ◽  
Acid Sensitivity ◽  
Urease Enzyme ◽  
H Pylori ◽  
Translational Level

Helicobacter hepaticus is a pathogen of rodents, which causes diverse enteric and hepatic inflammatory diseases and malignancies. The urease enzyme is an important colonization factor of gastric Helicobacter species like Helicobacter pylori, but little is known about the role and regulation of urease in enterohepatic Helicobacter species. Here it is reported that urease activity of H. hepaticus does not contribute to acid resistance, and that it is nickel-responsive at the post-translational level. H. hepaticus strain ATCC 51449 did not grow or survive at pH 3·0, and supplementation with urea or NiCl2 did not abrogate this acid sensitivity. Furthermore, urease enzyme activity of H. hepaticus was acid-independent, which contrasts with the acid-induced urease system of H. pylori. Nickel supplementation of Brucella medium resulted in a tenfold increase in urease activity in both H. hepaticus and H. pylori, but the maximum level of urease activity in H. hepaticus was still three- to fivefold lower when compared to H. pylori in the same conditions. The increase in urease activity of H. hepaticus was not associated with elevation of urease mRNA or protein levels. Inhibition of protein synthesis by chloramphenicol did not affect nickel-responsive induction of urease activity in H. hepaticus, and confirmed that nickel induction occurs at the post-translational level, probably by activation of preformed apo-enzyme. In conclusion, both the role of the urease enzyme and the regulation of urease activity differ between the enterohepatic pathogen H. hepaticus and the gastric pathogen H. pylori.

The rod-to-coccoid body transformation in cultures of Helicobacter pylori

1990 ◽  
Vol 48 (3) ◽  
pp. 626-627
Author(s):  
A. R. Crooker ◽  
W. G. Kraft ◽  
T. L. Beard ◽  
M. C. Myers
Keyword(s):  
Helicobacter Pylori ◽  
Growth Cycle ◽  
Negative Bacterium ◽  
Body Formation ◽  
Coccoid Form ◽  
Spiral Form ◽  
Prolonged Culture ◽  
H Pylori ◽  
Upper Gastrointestinal

Helicobacter pylori is a microaerophilic, gram-negative bacterium found in the upper gastrointestinal tract of humans. There is strong evidence that H. pylori is important in the etiology of gastritis; the bacterium may also be a major predisposing cause of peptic ulceration. On the gastric mucosa, the organism exists as a spiral form with one to seven sheathed flagella at one (usually) or both poles. Short spirals were seen in the first successful culture of the organism in 1983. In 1984, Marshall and Warren reported a coccoid form in older cultures. Since that time, other workers have observed rod and coccal forms in vitro; coccoid forms predominate in cultures 3-7 days old. We sought to examine the growth cycle of H. pylori in prolonged culture and the mode of coccoid body formation.

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