scholarly journals In Vitro Activity of Sertraline, an Antidepressant, Against Antibiotic-Susceptible and Antibiotic-Resistant Helicobacter pylori Strains

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 228 ◽  
Author(s):  
Paweł Krzyżek ◽  
Roman Franiczek ◽  
Barbara Krzyżanowska ◽  
Łukasz Łaczmański ◽  
Paweł Migdał ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Morphological Transformation ◽  
Gastric Diseases ◽  
Additive Interaction ◽  
Antibiotic Resistant ◽  
Minimal Inhibitory Concentrations ◽  
Killing Assay ◽  
H Pylori ◽  
Light Fluorescence

Antibiotic resistance of Helicobacter pylori, a spiral bacterium associated with gastric diseases, is a topic that has been intensively discussed in last decades. Recent discoveries indicate promising antimicrobial and antibiotic-potentiating properties of sertraline (SER), an antidepressant substance. The aim of the study, therefore, was to determine the antibacterial activity of SER in relation to antibiotic-sensitive and antibiotic-resistant H. pylori strains. The antimicrobial tests were performed using a diffusion-disk method, microdilution method, and time-killing assay. The interaction between SER and antibiotics (amoxicillin, clarithromycin, tetracycline, and metronidazole) was determined by using a checkerboard method. In addition, the study was expanded to include observations by light, fluorescence, and scanning electron microscopy. The growth inhibition zones were in the range of 19–37 mm for discs impregnated with 2 mg of SER. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) counted for 2–8 µg/mL and 4–8 µg/mL, respectively. The time-killing assay showed the time-dependent and concentration-dependent bactericidal activity of SER. Bacteria exposed to MBCs (but not sub-MICs and MICs ≠ MBCs) underwent morphological transformation into coccoid forms. This mechanism, however, was not protective because these cells after a 24-h incubation had a several-fold reduced green/red fluorescence ratio compared to the control. Using the checkerboard assay, a synergistic/additive interaction of SER with all four antibiotics tested was demonstrated. These results indicate that SER may be a promising anti-H. pylori compound.

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 Myricetin as an Antivirulence Compound Interfering with a Morphological Transformation into Coccoid Forms and Potentiating Activity of Antibiotics against Helicobacter pylori

2021 ◽  
Vol 22 (5) ◽  
pp. 2695
Author(s):  
Paweł Krzyżek ◽  
Paweł Migdał ◽  
Emil Paluch ◽  
Magdalena Karwańska ◽  
Alina Wieliczko ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Biofilm Formation ◽  
Inhibitory Effect ◽  
Morphological Transformation ◽  
High Tendency ◽  
Minimal Inhibitory Concentrations ◽  
Coccoid Form ◽  
Stomach Diseases ◽  
Fold Reduction ◽  
H Pylori

Helicobacter pylori, a gastric pathogen associated with a broad range of stomach diseases, has a high tendency to become resistant to antibiotics. One of the most important factors related to therapeutic failures is its ability to change from a spiral to a coccoid form. Therefore, the main aim of our original article was to determine the influence of myricetin, a natural compound with an antivirulence action, on the morphological transformation of H. pylori and check the potential of myricetin to increase the activity of antibiotics against this pathogen. We observed that sub-minimal inhibitory concentrations (sub-MICs) of this compound have the ability to slow down the process of transformation into coccoid forms and reduce biofilm formation of this bacterium. Using checkerboard assays, we noticed that the exposure of H. pylori to sub-MICs of myricetin enabled a 4–16-fold reduction in MICs of all classically used antibiotics (amoxicillin, clarithromycin, tetracycline, metronidazole, and levofloxacin). Additionally, RT-qPCR studies of genes related to the H. pylori morphogenesis showed a decrease in their expression during exposure to myricetin. This inhibitory effect was more strongly seen for genes involved in the muropeptide monomers shortening (csd3, csd6, csd4, and amiA), suggesting their significant participation in the spiral-to-coccoid transition. To our knowledge, this is the first research showing the ability of any compound to synergistically interact with all five antibiotics against H. pylori and the first one showing the capacity of a natural substance to interfere with the morphological transition of H. pylori from spiral to coccoid forms.

scholarly journals A peptide of a type I toxin-antitoxin system induces Helicobacter pylori morphological transformation from spiral-shape to coccoids

2019 ◽  
Author(s):  
Lamya El Mortaji ◽  
Alejandro Tejada-Arranz ◽  
Aline Rifflet ◽  
Ivo G Boneca ◽  
Gérard Pehau-Arnaudet ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Helicobacter Pylori ◽  
Membrane Integrity ◽  
Type I ◽  
Morphological Transformation ◽  
Bacterial Chromosomes ◽  
Concentration Result ◽  
H Pylori ◽  
Plasmid Stabilization

SummaryToxin-antitoxin systems are found in many bacterial chromosomes and plasmids with roles ranging from plasmid stabilization to biofilm formation and persistence. In these systems, the expression/activity of the toxin is counteracted by an antitoxin, which in type I systems is an antisense-RNA. While the regulatory mechanisms of these systems are mostly well-defined, the toxins’ biological activity and expression conditions are less understood. Here, these questions were investigated for a type I toxin-antitoxin system (AapA1-IsoA1) expressed from the chromosome of the human pathogen Helicobacter pylori. We show that expression of the AapA1 toxin in H. pylori causes growth arrest associated with rapid morphological transformation from spiral-shaped bacteria to round coccoid cells. Coccoids are observed in patients and during in vitro growth as a response to different stress conditions. The AapA1 toxin, first molecular effector of coccoids to be identified, targets H. pylori inner membrane without disrupting it, as visualized by Cryo-EM. The peptidoglycan composition of coccoids is modified with respect to spiral bacteria. No major changes in membrane potential or ATP concentration result from AapA1 expression, suggesting coccoid viability. Single-cell live microscopy tracking the shape conversion suggests a possible association of this process with cell elongation/division interference. Oxidative stress induces coccoid formation and is associated with repression of the antitoxin promoter and enhanced processing of its transcript, leading to an imbalance in favor of AapA1 toxin expression.Our data support the hypothesis of viable coccoids with characteristics of dormant bacteria that might be important in H. pylori infections refractory to treatment.Significance StatementHelicobacter pylori, a gastric pathogen causing 800,000 deaths in the world annually, is encountered both in vitro and in patients as spiral-shaped bacteria and as round cells named coccoids. We discovered that the toxin from a chromosomal type I toxin-antitoxin system is targeting H. pylori membrane and acting as an effector of H. pylori morphological conversion to coccoids. We showed that these round cells maintain their membrane integrity and metabolism, strongly suggesting that they are viable dormant bacteria. Oxidative stress was identified as a signal inducing toxin expression and coccoid formation. Our findings reveal new insights into a form of dormancy of this bacterium that might be associated with H. pylori infections refractory to treatment.

scholarly journals Functional Analysis of the cag Pathogenicity Island in Helicobacter pylori Isolates from Patients with Gastritis, Peptic Ulcer, and Gastric Cancer

2004 ◽  
Vol 72 (2) ◽  
pp. 1043-1056 ◽  
Author(s):  
Steffen Backert ◽  
Tobias Schwarz ◽  
Stephan Miehlke ◽  
Christian Kirsch ◽  
Christian Sommer ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Peptic Ulcer ◽  
Pathogenicity Island ◽  
Epidemiological Studies ◽  
Disease Development ◽  
Gastric Diseases ◽  
H Pylori ◽  
Gastric Cancer Patients

ABSTRACT Helicobacter pylori is the causative agent of a variety of gastric diseases, but the clinical relevance of bacterial virulence factors is still controversial. Virulent strains carrying the cag pathogenicity island (cagPAI) are thought to be key players in disease development. Here, we have compared cagPAI-dependent in vitro responses in H. pylori isolates obtained from 75 patients with gastritis, peptic ulcer, and gastric cancer (n = 25 in each group). AGS gastric epithelial cells were infected with each strain and assayed for (i) CagA expression, (ii) translocation and tyrosine phosphorylation of CagA, (iii) c-Src inactivation, (iv) cortactin dephosphorylation, (v) induction of actin cytoskeletal rearrangements associated with cell elongation, (vi) induction of cellular motility, and (vii) secretion of interleukin-8. Interestingly, we found high but similar prevalences of all of these cagPAI-dependent host cell responses (ranging from 56 to 80%) among the various groups of patients. This study revealed CagA proteins with unique features, CagA subspecies of various sizes, and new functional properties for the phenotypic outcomes. We further showed that induction of AGS cell motility and elongation are two independent processes. Our data corroborate epidemiological studies, which indicate a significant association of cagPAI presence and functionality with histopathological findings in gastritis, peptic ulcer, and gastric cancer patients, thus emphasizing the importance of the cagPAI for the pathogenicity of H. pylori. Nevertheless, we found no significant association of the specific H. pylori-induced responses with any particular patient group. This may indicate that the determination of disease development is highly complex and involves multiple bacterial and/or host factors.

scholarly journals Antibiofilm and Antimicrobial-Enhancing Activity of Chelidonium majus and Corydalis cheilanthifolia Extracts against Multidrug-Resistant Helicobacter pylori

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1033
Author(s):  
Paweł Krzyżek ◽  
Adam Junka ◽  
Wojciech Słupski ◽  
Arleta Dołowacka-Jóźwiak ◽  
Bartosz J. Płachno ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Drug Carrier ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Clinical Strain ◽  
Antibiofilm Activity ◽  
Chelidonium Majus ◽  
Minimal Inhibitory Concentrations ◽  
H Pylori

Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach of about 60% of people worldwide. The search for new drugs with activity against H. pylori is now a hotspot in the effective and safe control of this bacterium. Therefore, the aim of this research was to determine the antibacterial activity of extracts from selected plants of the Papaveraceae family against planktonic and biofilm forms of the multidrug-resistant clinical strain of H. pylori using a broad spectrum of analytical in vitro methods. It was revealed that among the tested extracts, those obtained from Corydalis cheilanthifolia and Chelidonium majus were the most active, with minimal inhibitory concentrations (MICs) of 64 µg/mL and 128 µg/mL, respectively. High concentrations of both extracts showed cytotoxicity against cell lines of human hepatic origin. Therefore, we attempted to lower their MICs through the use of a synergistic combination with synthetic antimicrobials as well as by applying cellulose as a drug carrier. Using checkerboard assays, we determined that both extracts presented synergistic interactions with amoxicillin (AMX) and 3-bromopyruvate (3-BP) (FICI = 0.5) and additive relationships with sertraline (SER) (FICI = 0.75). The antibiofilm activity of extracts and their combinations with AMX, 3-BP, or SER, was analyzed by two methods, i.e., the microcapillary overgrowth under flow conditions (the Bioflux system) and assessment of the viability of lawn biofilms after exposure to drugs released from bacterial cellulose (BC) carriers. Using both methods, we observed a several-fold decrease in the level of H. pylori biofilm, indicating the ability of the tested compounds to eradicate the microbial biofilm. The obtained results indicate that application of plant-derived extracts from the Papaveraceae family combined with synthetic antimicrobials, absorbed into organic BC carrier, may be considered a promising way of fighting biofilm-forming H. pylori.

scholarly journals In Silico Screening and In Vitro Assessment of Natural Products with Anti-Virulence Activity against Helicobacter pylori

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 20
Author(s):  
Maciej Spiegel ◽  
Paweł Krzyżek ◽  
Ewa Dworniczek ◽  
Ryszard Adamski ◽  
Zbigniew Sroka
Keyword(s):  
Helicobacter Pylori ◽  
In Silico ◽  
Stringent Response ◽  
Human Pathogens ◽  
Gastric Diseases ◽  
Natural Substances ◽  
Interesting Candidate ◽  
H Pylori ◽  
Static Conditions

Helicobacter pylori is one of the most frequent human pathogens and a leading etiological agent of various gastric diseases. As stringent response, coordinated by a SpoT protein, seems to be crucial for the survivability of H. pylori, the main goal of this article was to use in silico computational studies to find phytochemical compounds capable of binding to the active site of SpoT from H. pylori and confirm the ability of the most active candidates to interfere with the virulence of this bacterium through in vitro experiments. From 791 natural substances submitted for the virtual screening procedure, 10 were chosen and followed for further in vitro examinations. Among these, dioscin showed the most interesting parameters (the lowest MIC, the highest anti-biofilm activity in static conditions, and a relatively low stimulation of morphological transition into coccoids). Therefore, in the last part, we extended the research with a number of further experiments and observed the ability of dioscin to significantly reduce the formation of H. pylori biofilm under Bioflux-generated flow conditions and its capacity for additive enhancement of the antibacterial activity of all three commonly used antibiotics (clarithromycin, metronidazole, and levofloxacin). Based on these results, we suggest that dioscin may be an interesting candidate for new therapies targeting H. pylori survivability and virulence.

The Role of E-cadherin in Helicobacter pylori-Related Gastric Diseases

2019 ◽  
Vol 20 (1) ◽  
pp. 23-28
Author(s):  
Yunzhan Zhang ◽  
Danyan Li ◽  
Yunkai Dai ◽  
Ruliu Li ◽  
Yong Gao ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Precancerous Lesions ◽  
Research Literature ◽  
Gastric Diseases ◽  
H Pylori ◽  
The Relationship ◽  
E Cadherin

Background: Helicobacter pylori (H. pylori)-related gastric diseases are a series of gastric mucosal disorders associated with H. pylori infection. Gastric cancer (GC) is widely believed to evolve from gastritis and gastric ulcer. As an important adhesion molecule of epithelial cells, E-cadherin plays a key role in the development of gastric diseases. In this review, we aim to seek the characteristic of E-cadherin expression at different stages of gastric diseases. Methods: We searched plenty of databases for research literature about E-cadherin expression in H. pylori-related gastric diseases, and reviewed the relationship of E-cadherin and H. pylori, and the role of E-cadherin at different stages of gastric diseases. Results: H. pylori was shown to decrease E-cadherin expression by various ways in vitro, while most of clinical studies have not found the relationship between H. pylori and E-cadherin expression. It is defined that poor outcome of GC is related to loss expression of E-cadherin, but it is still unclear when qualitative change of E-cadherin expression in gastric mucosa emerges. Conclusion: Expression level of E-cadherin in gastric cells may be a consequence of injury factors and body’s selfrepairing ability. More studies on E-cadherin expression in gastric mucosa with precancerous lesions need to be performed, which may be potential and useful for early detection, prevention and treatment of GC.

scholarly journals The Effects of Sulglycotide on the Adhesion and the Inflammation of Helicobacter Pylori

2020 ◽  
Vol 17 (8) ◽  
pp. 2918
Author(s):  
Ji Yeong Yang ◽  
Pumsoo Kim ◽  
Seok-Hoo Jeong ◽  
Seong Woong Lee ◽  
Yu Sik Myung ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Protein A ◽  
Enzyme Linked Immunosorbent Assay ◽  
Etiologic Factor ◽  
Dilution Method ◽  
Gastric Diseases ◽  
Ags Cells ◽  
Human Gastric Adenocarcinoma ◽  
H Pylori

Helicobacter pylori (H. pylori) is a primary etiologic factor in gastric diseases. Sulglycotide is a glycopeptide derived from pig duodenal mucin. Esterification of its carbohydrate chains with sulfate groups creates a potent gastroprotective agent used to treat various gastric diseases. We investigated the inhibitory effects of sulglycotide on adhesion and inflammation after H. pylori infection in human gastric adenocarcinoma cells (AGS cells). H. pylori reference strain 60190 (ATCC 49503) was cultured on Brucella agar supplemented with 10% bovine serum. Sulgylcotide-mediated growth inhibition of H. pylori was evaluated using the broth dilution method. Inhibition of H. pylori adhesion to AGS cells by sulglycotide was assessed using a urease assay. Effects of sulglycotide on the translocation of virulence factors was measured using western blot to detect cytotoxin-associated protein A (CagA) and vacuolating cytotoxin A (VacA) proteins. Inhibition of IL-8 secretion was measured using enzyme-linked immunosorbent assay (ELISA) to determine the effects of sulglycotide on inflammation. Sulglycotide did not inhibit the growth of H. pylori, however, after six and 12 hours of infection on AGS cells, H. pylori adhesion was significantly inhibited by approximately 60% by various concentrations of sulglycotide. Sulglycotide decreased H. pylori virulence factor (CagA and VacA) translocation to AGS cells and inhibited IL-8 secretion. Sulglycotide inhibited H. pylori adhesion and inflammation after infection of AGS cells in vitro. These results support the use of sulglycotide to treat H. pylori infections.

scholarly journals In Vitro Activity of 3-Bromopyruvate, an Anticancer Compound, Against Antibiotic-Susceptible and Antibiotic-Resistant Helicobacter pylori Strains

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 229 ◽  
Author(s):  
Paweł Krzyżek ◽  
Roman Franiczek ◽  
Barbara Krzyżanowska ◽  
Łukasz Łaczmański ◽  
Paweł Migdał ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Bactericidal Activity ◽  
Detection Threshold ◽  
Diffusion Method ◽  
Antibiotic Resistant ◽  
Killing Assay ◽  
Broth Microdilution Method ◽  
Checkerboard Assay ◽  
H Pylori ◽  
Anticancer Compound

Helicobacter pylori (H. pylori) is a bacterium capable of inducing chronic active gastritis, which in some people, develops into gastric cancers. One of the substances that may be useful in the eradication of this microorganism is 3-Bromopyruvate (3-BP), an anticancer compound with antimicrobial properties. The aim of this article was to determine the activity of 3-BP against antibiotic-susceptible and antibiotic-resistant H. pylori strains. The antimicrobial activity was determined using a disk-diffusion method, broth microdilution method, time-killing assay, and checkerboard assay. The research was extended by observations using light, fluorescence, and scanning electron microscopy. The growth inhibition zones produced by 2 mg/disk with 3-BP counted for 16–32.5 mm. The minimal inhibitory concentrations (MICs) ranged from 32 to 128 μg/mL, while the minimal bactericidal concentrations (MBCs) for all tested strains had values of 128 μg/mL. The time-killing assay demonstrated the concentration-dependent and time-dependent bactericidal activity of 3-BP. The decrease in culturability below the detection threshold (<100 CFU/mL) was demonstrated after 6 h, 4 h, and 2 h of incubation for MIC, 2× MIC, and 4× MIC, respectively. Bacteria treated with 3-BP had a several times reduced mean green/red fluorescence ratio compared to the control samples, suggesting bactericidal activity, which was independent from an induction of coccoid forms. The checkerboard assay showed the existence of a synergistic/additive interaction of 3-BP with amoxicillin, tetracycline, and clarithromycin. Based on the presented results, it is suggested that 3-BP may be an interesting anti-H. pylori compound.

scholarly journals Antibacterial action of acriflavine hydrochloride for eradication of the gastric pathogen Helicobacter pylori

2020 ◽  
Vol 367 (21) ◽  
Author(s):  
Ankita Tehlan ◽  
Bipul Chandra Karmakar ◽  
Sangita Paul ◽  
Raghwan Kumar ◽  
Inderjeet Kaur ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Synergistic Effect ◽  
Clinical Isolates ◽  
The Novel ◽  
Mice Model ◽  
Antibiotic Resistant ◽  
Low Concentrations ◽  
H Pylori

ABSTRACT Helicobacter pylori, a type 1 carcinogen, accounts for numerous gastric cancer-related deaths worldwide. Repurposing existing drugs or developing new ones for a combinatorial approach against increasing antimicrobial resistance is the need of the hour. This study highlights the efficacy of acriflavine hydrochloride (ACF-HCl) in inhibiting the growth of H. pylori reference strain and antibiotic-resistant clinical isolates at low concentrations. ACF-HCl inhibits H. pylori growth at MIC value 10 times less than that in Escherichia coli, another Gram-negative bacteria. Furthermore, ACF-HCl demonstrates synergistic effect with clarithromycin, a commonly used antibiotic against H. pylori. ACF-HCl treatment also eradicates H. pylori infection in the mice model efficiently. Our in vitro data indicate that bacterial membrane is the prime target. The novel action of ACF-HCl against antibiotic-resistant clinical isolates, synergistic effect with the conventional antibiotic clarithromycin and eradication of H. pylori from infected mice highlight the potential of ACF-HCl as a promising therapeutic agent against H. pylori by itself as well as for combinatorial therapy.

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