Dihydrotanshinone I Is Effective against Drug-Resistant Helicobacter pylori In Vitro and In Vivo.
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ABSTRACT:
SUBMITTER: Luo P
PROVIDER: S-EPMC8092497 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6963513 | biostudies-literature
Project description:Helicobacter pylori is a major global pathogen, and its infection represents a key factor in the etiology of various gastric diseases, including gastritis, peptic ulcers, and gastric carcinoma. The efficacy of current standard treatment for H. pylori infection including two broad-spectrum antibiotics is compromised by toxicity toward the gut microbiota and the development of drug resistance, which will likely only be resolved through novel and selective antibacterial strategies. Here, we synthesized a small molecule, zinc linolenate (ZnLla), and investigated its therapeutic potential for the treatment of H. pylori infection. ZnLla showed effective antibacterial activity against standard strains and drug-resistant clinical isolates of H. pyloriin vitro with no development of resistance during continuous serial passaging. The mechanisms of ZnLla action against H. pylori involved the disruption of bacterial cell membranes and generation of reactive oxygen species. In mouse models of multidrug-resistant H. pylori infection, ZnLla showed in vivo killing efficacy comparable and superior to the triple therapy approach when use as a monotherapy and a combined therapy with omeprazole, respectively. Moreover, ZnLla treatment induces negligible toxicity against normal tissues and causes minimal effects on both the diversity and composition of the murine gut microbiota. Thus, the high degree of selectivity of ZnLla for H. pylori provides an attractive candidate for novel targeted anti-H. pylori treatment.
| S-EPMC6535540 | biostudies-literature
Project description: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.
| S-EPMC6406402 | biostudies-literature
Project description: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.
| S-EPMC5444145 | biostudies-literature
Project description: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.
| S-EPMC7179623 | biostudies-literature
Project description:beta-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded blaC gene product. The carbapenem class of beta-lactams are very poor substrates for BlaC, allowing us to determine the three-dimensional structure of the covalent BlaC-meropenem covalent complex at 1.8 angstrom resolution. When meropenem was combined with the beta-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [minimum inhibitory concentration (MIC(meropenem)) less than 1 microgram per milliliter], and sterilization of aerobically grown cultures was observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the "persistent" state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. Meropenem and clavulanate are Food and Drug Administration-approved drugs and could potentially be used to treat patients with currently untreatable disease.
| S-EPMC2679150 | biostudies-other
Project description:The most evident challenge to treatment of Helicobacter pylori, a bacterium responsible for gastritis, peptic ulcers and gastric cancer, is the increasing rate of resistance to all currently used therapeutic antibiotics. Thus, the development of novel therapies is urgently required. N-geranyl-N'-(2-adamantyl) ethane-1, 2-diamine (SQ109) is an ethylene diamine-based antitubercular drug that is currently in clinical trials for the treatment of tuberculosis (TB). Previous pharmacokinetic studies of SQ109 revealed that persistently high concentrations of SQ109 remain in the stomach 4 hours post oral administration in rats. This finding, combined with the need for new anti-Helicobacter therapies, prompted us to define the in vitro efficacy of SQ109 against H. pylori. Liquid broth micro-dilution was used for susceptibility studies to determine the antimicrobial activity of SQ109 against a total of 6 laboratory strains and 20 clinical isolates of H. pylori; the clinical isolates included a multi-drug resistant strain. All strains tested were susceptible to SQ109 with MIC and MBC ranges of 6-10 µM and 50-60 µM, respectively. SQ109 killing kinetics were concentration- and time-dependent. SQ109 killed H. pylori in 8-10 h at 140 µM (2MBCs) or 4-6 h at 200 µM (~3MBCs). Importantly, though the kinetics of killing were altered, SQ109 retained potent bactericidal activity against H. pylori at low pH. Additionally, SQ109 demonstrated robust thermal stability and was effective at killing slow growing or static bacteria. In fact, pretreatment of cultures with a bacteriostatic concentration of chloramphenicol (Cm) synergized the effects of typically bacteriostatic concentrations of SQ109 to the level of five-logs of bacterial killing. A molar-to-molar comparison of the efficacy of SQ109 as compared to metronidazole (MTZ), amoxicillin (AMX), rifampicin (RIF) and clarithromycin (CLR), revealed that SQ109 was superior to MTZ, AMX and RIF but not to CLR. Finally, the frequency of resistance to SQ109 was low and electron microscopy studies revealed that SQ109 interacted with bacterial inner membrane and cytoplasmic content(s). Collectively, our in vitro data demonstrate that SQ109 is an effective monotherapy against susceptible and multi-drug resistant strains of H. pylori and may be useful alone or in combination with other antibiotics for development as a new class of anti-Helicobacter drugs.
| S-EPMC3723868 | biostudies-literature
Project description:The human specific bacterial pathogen Helicobacter pylori (H. pylori) is associated with severe gastric diseases, including gastric cancer. Recently, the increasing resistance makes the usage of antibiotics less effectively. Therefore, development of a new antimicrobial agent is required to control H. pylori infection. In the current study, the inhibitory effect of β-caryophyllene on H. pylori growth, as well as the antibacterial therapeutic effect, has been demonstrated. β-caryophyllene inhibited H. pylori growth via the downregulation of dnaE, dnaN, holB, and gyrA and also downregulated virulence factors such as CagA, VacA, and SecA proteins. β-caryophyllene inhibited expression of several T4SS components, so that CagA translocation into H. pylori-infected AGS gastric cancer cells was decreased by β-caryophyllene treatment. β-caryophyllene also inhibited VacA entry through the downregulation of T5aSS. After β-caryophyllene administration on Mongolian gerbils, the immunohistochemistry (IHC) and Hematoxylin&Eosin stains showed therapeutic effects in the treated groups. Hematological data, which was consistent with histological data, support the therapeutic effect of β-caryophyllene administration. Such a positive effect of β-caryophyllene on H. pylori infection potently substantiates the natural compound as being capable of being used as a new antimicrobial agent or functional health food to help patients who are suffering from gastroduodenal diseases due to H. pylori infection.
| S-EPMC7037973 | biostudies-literature
Project description:Helicobacter pylori causes gastritis, peptic ulcers and gastric cancer and affects more than half of the world's population. Although this infection can have serious consequences, no novel cure or remedy have been discovered, the present therapy still relies on a variety of known antibiotics and anti-secretory agents. In the present study, the potential effect of combinations between methanolic extracts of four Algerian medicinal plants, garlic (Allium sativum), red onion (Allium cepa), cumin (Cuminum cyminum L.) and fenugreek (T. foenum-graecum L.), with different strains of lactic acid bacteria against H. pylori, was investigated. Similarly, the in vivo antibacterial effect of fenugreek extract combined with Bifidobacterium breve on H. pylori colonization potential to confirm the enhanced effect of the mixture was explored. Helicobacter pylori was inhibited by all combined mixtures of extracts and probiotics with varying results. The highest anti-H. pylori activities were found in fenugreek/B. breve, cumin/B. breve, garlic/B. breve and onion/B. breve combinations with inhibition diameters of 29, 26, 23 and 25 mm, respectively. Preliminary studies on the effect of probiotics against H. pylori revealed that the inhibition was due to lactic acid and bacteriocins and it was also related to the presence of phenolic compounds in the studied plants, such as gallic acid, caffeic acid, quercetin and vanillic acid. Fenugreek extract was found to inhibit the growth of H. pylori in a concentration-dependent manner. When H. pylori-infected rats were administered B. breve, the infection rate of H. pylori was significantly reduced, while the combination of B. breve and fenugreek extract effectively inhibited H. pylori. In addition, the B. breve and fenugreek extract mixture significantly reduced gastritis in H. pylori-infected rats. These results suggest that this complex mixture may be an alternative to treating diseases caused by H. pylori infection.
| S-EPMC10224446 | biostudies-literature
Project description:Helicobacter pylori is a Gram-negative bacterium that colonizes the gut of over 50% of the world's population. It is responsible for most peptic ulcers and is an important risk factor for gastric cancer. Antibiotic treatment for H. pylori infections is challenging as drug resistance has developed to antibiotics with traditional mechanisms of action. H. pylori uses an unusual pathway for menaquinone biosynthesis with 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzing an essential step. We validated MTAN as a target with a transition-state analogue of the enzyme [Wang, S.; Haapalainen, A. M.; Yan, F.; et al. Biochemistry 2012, 51, 6892-6894]. MTAN inhibitors will only be useful drug candidates if they can both include tight binding to the MTAN target and have the ability to penetrate the complex cell membrane found in Gram-negative H. pylori. Here we explore structural scaffolds for MTAN inhibition and for growth inhibition of cultured H. pylori. Sixteen analogues reported here are transition-state analogues of H. pylori MTAN with dissociation constants of 50 pM or below. Ten of these prevent growth of the H. pylori with IC90 values below 0.01 μg/mL. These remarkable compounds meet the criteria for potent inhibition and cell penetration. As a consequence, 10 new H. pylori antibiotic candidates are identified, all of which prevent H. pylori growth at concentrations 16-2000-fold lower than the five antibiotics, amoxicillin, metronidazole, levofloxacin, tetracyclin, and clarithromycin, commonly used to treat H. pylori infections. X-ray crystal structures of MTAN cocrystallized with several inhibitors show them to bind in the active site making interactions consistent with transition-state analogues.
| S-EPMC6709534 | biostudies-literature