Punicalagin, a pomegranate polyphenol sensitizes the activity of antibiotics against three MDR pathogens of the Enterobacteriaceae
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SUBMITTER: Kiran S
PROVIDER: S-EPMC10870630 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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| S-EPMC11241309 | biostudies-literature
Project description:BackgroundPunicalagin is the major phenolic compound found in pomegranate peels. It has several reported medical benefits, including antioxidant, anti-inflammatory, and anticancer properties. The present study investigated the anti-leukemic effects and the molecular mechanism of punicalagin on NB4 and MOLT-4 leukemic cell lines.MethodsLeukemic cells were treated with punicalagin and cell viability was determined using MTS assay. Apoptosis and autophagy were analyzed by flow cytometry using Annexin V-FITC/PI and anti-LC3/FITC antibodies staining, respectively. Apoptotic and autophagic mRNA expression were determined using reverse transcription-quantitative PCR. STITCH bioinformatics tools were used to predict the interaction between punicalagin and its proposed target proteins.ResultsResults indicated that punicalagin decreased NB4 and MOLT-4 cell viability in a dose-dependent manner. Punicalagin, in combination with daunorubicin, exhibited synergistic cytotoxic effects. Punicalagin induced apoptosis through the upregulation of caspase-3/-8/-9, Bax and the downregulation of Bcl-2 expression. Punicalagin also promoted autophagy via the downregulation of mTOR and the upregulation of ULK1 expression. Cyclooxygenase-2 and toll-like receptor 4 were found to be involved in punicalagin-induced cell death in punicalagin-targeted protein interactions.ConclusionsThese results suggest that punicalagin exerts cytotoxic activities by suppressing proliferation and promoting apoptosis and autophagy by activating the caspase cascade, altering Bax and Bcl-2, and regulating autophagy via mTOR/ULK1 signaling.
| S-EPMC8570173 | biostudies-literature
Project description:The increasing use of polymyxins1 in addition to the dissemination of plasmid-borne colistin resistance threatens to cause a serious breach in our last line of defence against multidrug-resistant Gram-negative pathogens, and heralds the emergence of truly pan-resistant infections. Colistin resistance often arises through covalent modification of lipid A with cationic residues such as phosphoethanolamine-as is mediated by Mcr-1 (ref. 2)-which reduce the affinity of polymyxins for lipopolysaccharide3. Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections4. The difficulty in eradicating Gram-negative bacteria is largely due to their highly impermeable outer membrane, which serves as a barrier to many otherwise effective antibiotics5. Here, we describe an unconventional screening platform designed to enrich for non-lethal, outer-membrane-active compounds with potential as adjuvants for conventional antibiotics. This approach identified the antiprotozoal drug pentamidine6 as an effective perturbant of the Gram-negative outer membrane through its interaction with lipopolysaccharide. Pentamidine displayed synergy with antibiotics typically restricted to Gram-positive bacteria, yielding effective drug combinations with activity against a wide range of Gram-negative pathogens in vitro, and against systemic Acinetobacter baumannii infections in mice. Notably, the adjuvant activity of pentamidine persisted in polymyxin-resistant bacteria in vitro and in vivo. Overall, pentamidine and its structural analogues represent unexploited molecules for the treatment of Gram-negative infections, particularly those having acquired polymyxin resistance determinants.
| S-EPMC5360458 | biostudies-literature
Project description:Natural antioxidants products are widely distributed in food and medicinal plants. These natural antioxidants, especially polyphenols, exhibit a wide range of biological activities including anti-cancer, anti-inflammatory, and anti-atherosclerosis activities. Pomegranate (Punica granatum L.) is a rich source of polyphenolic components. The purpose of this study was to characterize the phenolic composition and flavonoids and anthocyanin content of different parts (peel and aril) of the Sefri variety of pomegranate. Our results showed that Peel extract was richer in these compounds than that of the Arils, especially in Punicalagin (A and B). DPPH free radical scavenging, reducing power (FRAP), β-carotene bleaching, and hydrogen peroxide scavenging assays revealed a greater dose-dependent activity of pomegranate peel phenolic extract (PPPE) compared to pomegranate aril phenolic extract (PAPE). PPPE was also more potent than PAPE concerning its ability to inhibit conjugated diene formation and to reduce α-tocopherol disappearance induced by CuSO4-mediated LDL peroxidation. Interestingly, both extracts (PPPE and PAPE) significantly inhibited lipid peroxidation and the formation of reactive oxygen species (ROS) in stressed J82 human bladder cancer cells. These results reflect the protective effects that this Moroccan variety of pomegranate can provide against the development of metabolic disorder, cancer, atherosclerosis, and cardiovascular disease. Given these properties, further studies should be undertaken to investigate possible applications of Sefri pomegranate extracts in the fields of food preservation and health supplements.
| S-EPMC8469689 | biostudies-literature
Project description:This study compared the activity of cefepime + zidebactam (FEP-ZID) and selected currently available antibacterial agents against a panel of multidrug-resistant (MDR) clinical isolates chosen to provide an extreme challenge for antibacterial activity. FEP⁻ZID had a very broad and potent in vitro spectrum of activity, and was highly active against many MDR isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. Notably, it inhibited isolates producing carbapenemases of Ambler classes A, B, and D, and P. aeruginosa isolates with multiple resistance mechanisms including combinations of upregulated efflux, diminished or non-functional OprD porins, and AmpC overproduction. Its clinical role will be determined initially by the breakpoints assigned to it, comparison studies with other investigational β-lactamase inhibitor combinations, and ultimately by the developing body of therapeutic outcome data.
| S-EPMC6466586 | biostudies-literature
Project description:The recent expansion of multidrug resistant and pan-drug-resistant pathogens poses significant challenges in the treatment of healthcare associated infections. An important advancement, is a handful of recently launched new antibiotics targeting some of the current most problematic Gram-negative pathogens, namely carbapenem-producing Enterobacteriaceae (CRE) and carbapenem-resistant P. aeruginosa (CRPA). Less options are available against carbapenem-resistant Acinetobacter baumannii (CRAB) and strains producing metallo-beta lactamases (MBL). Ceftazidime-avibactam signaled a turning point in the treatment of KPC and partly OXA- type carbapenemases, whereas meropenem-vaborbactam was added as a potent combination against KPC-producers. Ceftolozane-tazobactam could be seen as an ideal beta-lactam backbone for the treatment of CRPA. Plazomicin, an aminoglycoside with better pharmacokinetics and less toxicity compared to other class members, will cover important proportions of multi-drug resistant pathogens. Eravacycline holds promise in the treatment of infections by CRAB, with a broad spectrum of activity similar to tigecycline, and improved pharmacokinetics. Novel drugs and combinations are not to be considered "panacea" for the ongoing crisis in the therapy of XDR Gram-negative bacteria and colistin will continue to be considered as a fundamental companion drug for the treatment of carbapenem-resistant Enterobacteriaceae (particularly in areas where MBL predominate), for the treatment of CRPA (in many cases being the only in vitro active drug) as well as CRAB. Aminoglycosides are still important companion antibiotics. Finally, fosfomycin as part of combination treatment for CRE infections and P. aeruginosa, deserves a greater attention. Optimal conditions for monotherapy and the "when and how" of combination treatments integrating the novel agents will be discussed.
| S-EPMC6581067 | biostudies-literature
Project description:The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin 17S. Compared to humimycin A, 17S is a more potent β-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE), and did not lead to any detectable resistance when used in combination with a β-lactam. Combinations of β-lactam and humimycin 17S provide a potentially useful long-term MRSA regimen.
| S-EPMC7163398 | biostudies-literature
Project description:BackgroundOur recent study has shown that pomegranate peel extract (PEx) showed significant immunomodulatory activity, which might be caused by ellagitannins. The aim of this work was to test the hypothesis that ellagitannin components act synergistically in the modulation of cytokine production.MethodsHuman peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with phytohemagglutinin and treated with different concentrations of PEx or punicalagin (PG), punicalin (PN), and ellagic acid (EA), alone or with their combinations. Cytotoxicity, cell proliferation, and cytokine production were determined.ResultsNon-cytotoxic concentrations of all compounds significantly inhibited cell proliferation. IC50 values (μg/mL) were: EA (7.56), PG (38.52), PEx (49.05), and PN (69.95). PEx and all ellagitannins inhibited the levels of TNF-α, IL-6, and IL-8, dose-dependently, and their combinations acted synergistically. PEx and all ellagitannins inhibited Th1 and Th17 responses, whereas the lower concentrations of PEx stimulated the production of IL-10, a Treg cytokine, as did lower concentrations of EA. However, neither component of ellagitannins increased Th2 response, as was observed with PEx.ConclusionsThe combination of PG, PN, and EA potentiated the anti-inflammatory response without any significant synergistic down-modulatory effect on T-cell cytokines. The increased production of IL-10 observed with PEx could be attributable to EA, but the examined ellagitannins are not associated with the stimulatory effect of PEx on Th2 response.
| S-EPMC9695876 | biostudies-literature
Project description:Obesity is associated with an increasing prevalence of cardiovascular diseases and metabolic syndrome. It is of paramount importance to reduce obesity-associated cardiac dysfunction and impaired energy metabolism. In this study, the activation of the AMP-activated protein kinase (AMPK) pathway by punicalagin (PU), a major ellagitannin in pomegranate was investigated in the heart of a rat obesity model. In male SD rats, eight-week administration of 150 mg/kg pomegranate extract (PE) containing 40% punicalagin sufficiently prevented high-fat diet (HFD)-induced obesity associated accumulation of cardiac triglyceride and cholesterol as well as myocardial damage. Concomitantly, the AMPK pathway was activated, which may account for prevention of mitochondrial loss via upregulating mitochondrial biogenesis and amelioration of oxidative stress via enhancing phase II enzymes in the hearts of HFD rats. Together with the normalized expression of uncoupling proteins and mitochondrial dynamic regulators, PE significantly prevented HFD-induced cardiac ATP loss. Through in vitro cultures, we showed that punicalagin was the predominant component that activated AMPK by quickly decreasing the cellular ATP/ADP ratio specifically in cardiomyocytes. Our findings demonstrated that punicalagin, the major active component in PE, could modulate mitochondria and phase II enzymes through AMPK pathway to prevent HFD-induced cardiac metabolic disorders.
| S-EPMC4642696 | biostudies-literature
Project description:Antimicrobial resistance is a critical challenge due to the overuse of conventional antimicrobials, and alternative solutions are urgently needed. This study investigates the efficacy of compounds derived from lactic acid bacteria (LAB) fermentation combined with antibiotics against multidrug-resistant pathogens isolated from clinical cases in a hospital setting. Strains of Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecium and faecalis were isolated and selected from blood, respiratory, and urine samples. They were tested against the fermentation products from the Ingulados LAB collection (BAL5, BAL6, BAL8, BAL13, and BAL16), recognized for their antimicrobial efficacy against veterinary pathogens. The activity against multidrug-resistant (MDR) pathogens was evaluated initially, followed by synergy tests using checkerboard assays and subsequent analysis. Bioinformatic assessments and supernatant treatments were performed to characterize the nature of the compounds responsible for the antimicrobial activity. Notably, BAL16 exhibited significant growth inhibition against multidrug-resistant E. faecium. Synergy tests highlighted its combined activity with tetracycline through FICI and surface analysis and bioinformatic analysis unveiled the protein fraction containing bacteriocins as the underlying mechanism. This study highlights BAL16 fermentation products potential as valuable antimicrobial agents against MDR E. faecium infections, attributed to bacteriocins. Further in-depth studies are necessary for complete bacteriocin characterization.
| S-EPMC10967309 | biostudies-literature