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Frontiers in Microbiology 2022Antimicrobial resistance in clinically important microbes has emerged as an unmet challenge in global health. Extensively drug-resistant bacterial pathogens have cropped... (Review)
Review
Antimicrobial resistance in clinically important microbes has emerged as an unmet challenge in global health. Extensively drug-resistant bacterial pathogens have cropped up lately defying the action of even the last resort of antibiotics. This has led to a huge burden in the health sectors and increased morbidity and mortality rate across the world. The dwindling antibiotic discovery pipeline and rampant usage of antibiotics has set the alarming bells necessitating immediate actions to combat this looming threat. Various alternatives to discovery of new antibiotics are gaining attention such as reversing the antibiotic resistance and hence reviving the arsenal of antibiotics in hand. Antibiotic resistance reversal is mainly targeted against the antibiotic resistance mechanisms, which potentiates the effective action of the antibiotic. Such compounds are referred to as resistance breakers or antibiotic adjuvants/potentiators that work in conjunction with antibiotics. Many studies have been conducted for the identification of compounds, which decrease the permeability barrier, expression of efflux pumps and the resistance encoding enzymes. Compounds targeting the stability, inheritance and dissemination of the mobile genetic elements linked with the resistance genes are also potential candidates to curb antibiotic resistance. In pursuit of such compounds various natural sources and synthetic compounds have been harnessed. The activities of a considerable number of compounds seem promising and are currently at various phases of clinical trials. This review recapitulates all the studies pertaining to the use of antibiotic potentiators for the reversal of antibiotic resistance and what the future beholds for their usage in clinical settings.
PubMed: 35847117
DOI: 10.3389/fmicb.2022.887251 -
European Journal of Surgical Oncology :... Mar 2016Recent identification of a cancer stem cell (CSC) phenotype in solid tumors has greatly enhanced the understanding of the mechanisms responsible for cancer cell... (Review)
Review
Recent identification of a cancer stem cell (CSC) phenotype in solid tumors has greatly enhanced the understanding of the mechanisms responsible for cancer cell metastasis. In keeping with Pagets 'seed and soil' theory, CSCs display dependence upon stromal derived factors found within the niche in which they reside. Inflammatory mediators act as a 'fertilizer' within this niche when interacting with CSCs at the tumor-stromal interface and can potentiate the metastatic ability of CSCs. Interestingly, the same components of the pro-inflammatory milieu experienced by cancer patients perioperatively are known to promote the metastagenic potential of CSCs. On the basis of this observation we discuss how surgery-induced inflammation potentiates colon CSC involvement in the metastatic process. We hypothesize that the high rates of recurrence and metastasis associated with tumor resection are potentiated by the effects of surgery-induced inflammation on CSCs. Finally we discuss potential therapeutic strategies for use in the perioperative window to protect cancer patients from the oncological effects of the pro-inflammatory milieu.
Topics: Cell Proliferation; Female; Humans; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Sensitivity and Specificity; Stem Cell Niche
PubMed: 26810247
DOI: 10.1016/j.ejso.2015.12.008 -
Progress in Medicinal Chemistry 2018Cystic fibrosis (CF) is a genetic disorder driven by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While different mutations lead to... (Review)
Review
Cystic fibrosis (CF) is a genetic disorder driven by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While different mutations lead to varying levels of disease severity, the most common CFTR F508del mutation leads to defects in protein stability, trafficking to the cell membrane and gating of chloride ions. Recently, advances in medicinal chemistry have led to the identification small-molecule drugs that result in significant clinical efficacy in improving lung function in CF patients. Multiple CFTR modulators are required to fix the various defects in the CFTR protein. Small-molecule potentiators increase the open-channel probability and improve the gating of ions through CFTR. Small-molecule correctors stabilize the protein fold of the mutant channel, facilitating protein maturation and translocation to the cellular membrane. Recent data suggest that triple-combination therapy consisting of a potentiator and two correctors that operate through distinct mechanisms will be required to deliver highly significant clinical efficacy for most CF patients. The progress in medicinal chemistry that has led to the identification of novel CFTR potentiators and correctors is presented in this chapter.
Topics: Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Drug Discovery; Gene Expression Regulation; Humans
PubMed: 29680149
DOI: 10.1016/bs.pmch.2018.01.001 -
Plants (Basel, Switzerland) May 2022The secondary metabolites of endemic plants from the Rutaceae family, such as Burkillanthusmalaccensis (Ridl.) Swingle from the rainforest of Malaysia, has not been...
The secondary metabolites of endemic plants from the Rutaceae family, such as Burkillanthusmalaccensis (Ridl.) Swingle from the rainforest of Malaysia, has not been studied. Burkillanthusmalaccensis (Ridl.) Swingle may produce antibacterial and antibiotic-potentiating secondary metabolites. Hexane, chloroform, and methanol extracts of leaves, bark, wood, pericarps, and endocarps were tested against bacteria by broth microdilution assay and their antibiotic-potentiating activities. Chromatographic separations of hexane extracts of seeds were conducted to investigate effective phytochemicals and their antibacterial activities. Molecular docking studies of werneria chromene and dihydroxyacidissiminol against SARS-CoV-2 virus infection were conducted using AutoDock Vina. The methanol extract of bark inhibited the growth of Staphylococcusaureus, Escherichiacoli, and Pseudomonasaeruginosa with the minimum inhibitory concentration of 250, 500, and 250 µg/mL, respectively. The chloroform extract of endocarps potentiated the activity of imipenem against imipenem-resistant Acinetobacterbaumannii. The hexane extract of seeds increased the sensitivity of P. aeruginosa against ciprofloxacin and levofloxacin. The hexane extract of seeds and chloroform extract of endocarps were chromatographed, yielding werneria chromene and dihydroxyacidissiminol. Werneria chromene was bacteriostatic for P.aeruginosa and P.putida, with MIC/MBC values of 1000 > 1000 µg/mL. Dihydroxyacidissiminol showed the predicted binding energies of −8.1, −7.6, −7.0, and −7.5 kcal/mol with cathepsin L, nsp13 helicase, SARS-CoV-2 main protease, and SARS-CoV-2 spike protein receptor-binding domain S-RBD. Burkillanthusmalaccensis (Ridl.) Swingle can be a potential source of natural products with antibiotic-potentiating activity and that are anti-SARS-CoV-2.
PubMed: 35684161
DOI: 10.3390/plants11111388 -
Phytomedicine : International Journal... Dec 2017Biofilms contribute to the pathogenesis of many chronic and difficult-to eradicate infections whose treatment is complicated due to the intrinsic resistance to... (Review)
Review
BACKGROUND
Biofilms contribute to the pathogenesis of many chronic and difficult-to eradicate infections whose treatment is complicated due to the intrinsic resistance to conventional antibiotics. As a consequence, there is an urgent need for strategies that can be used for the prevention and treatment of biofilm-associated infections. The combination therapy comprising an antimicrobial drug with a low molecular weight (MW) natural product and an antimicrobial drug (antifungal or antibacterial) appeared as a good alternative to eradicate biofilms.
PURPOSE
The aims of this review were to perform a literature search on the different natural products that have showed the ability of potentiating the antibiofilm capacity of antimicrobial drugs, to analyze which are the antimicrobial drugs most used in combination, and to have a look on the microbial species most used to prepare biofilms.
RESULTS
Seventeen papers, nine on combinations against antifungal biofilms and eight against antibacterial biofilms were collected. Within the text, the following topics have been developed: breaf history of the discovery of biofilms; stages in the development of a biofilm; the most used methodologies to assess antibiofilm-activity; the natural products with capacity of eradicating biofilms when acting alone; the combinations of low MW natural products with antibiotics or antifungal drugs as a strategy for eradicating microbial biofilms and a list of the low MW natural products that potentiate the inhibition capacity of antifungal and antibacterial drugs against biofilms.
CONCLUSIONS AND PERSPECTIVES
Regarding combinations against antifungal biofilms, eight over the nine collected works were carried out with in vitro studies while only one was performed with in vivo assays by using Caenorhabditis elegans nematode. All studies use biofilms of the Candida genus. A 67% of the potentiators were monoterpenes and sesquiterpenes and six over the nine works used FCZ as the antifungal drug. The activity of AmpB and Caspo was enhanced in one and two works respectively. Regarding combinations against bacterial biofilms, in vitro studies were performed in all works by using several different methods of higher variety than the used against fungal biofilms. Biofilms of both the gram (+) and gram (-) bacteria were prepared, although biofilm of Staphylococcus spp. were the most used in the collected works. Among the discovered potentiators of antibacterial drugs, 75% were terpenes, including mono, di- and triterpenes, and, among the atibacterial drugs, several structurally diverse types were used in the combinations: aminoglycosides, β-lactams, glucopeptides and fluoroquinolones. The potentiating capacity of natural products, mainly terpenes, on the antibiofilm effect of antimicrobial drugs opens a wide range of possibilities for the combination antimicrobial therapy. More in vivo studies on combinations of natural products with antimicrobial drugs acting against biofilms are highly required to cope the difficult to treat biofilm-associated infections.
Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Bacteria; Biofilms; Biological Products; Fungi; Microbial Sensitivity Tests
PubMed: 29174600
DOI: 10.1016/j.phymed.2017.10.021 -
Frontiers in Molecular Neuroscience 2018Oxidized phospholipids (OxPL) like oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) were recently identified as novel proalgesic targets in acute...
Oxidized phospholipids (OxPL) like oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) were recently identified as novel proalgesic targets in acute and chronic inflammatory pain. These endogenous chemical irritants are generated in inflamed tissue and mediate their pain-inducing function by activating the transient receptor potential channels TRPA1 and TRPV1 expressed in sensory neurons. Notably, prototypical therapeutics interfering with OxPL were shown to inhibit TRP channel activation and pain behavior. Here, we asked how OxPL excite primary sensory neurons of dorsal root ganglia (DRG neurons from mice of either sex). Acute stimulation of sensory neurons with the prototypical OxPL 1-palmitoyl-2-glutaryl--glycero-3-phosphocholine (PGPC) evoked repetitive calcium spikes in small-diameter neurons. As Na1.9, a voltage-gated sodium channel involved in nociceptor excitability, was previously shown to be essential for the generation of calcium spikes in motoneurons, we asked if this channel is also important for OxPL mediated calcium spike and action potential generation in nociceptors. In wild-type and Na1.9-deficient neurons, the action potential firing rate and the calcium spike frequency to an acute PGPC stimulus was similar. When preincubated with inflammatory mediators, both, the action potential firing rate and the calcium spike frequency were markedly increased in response to an acute PGPC stimulus. However, this potentiating effect was completely lost in Na1.9-deficient small-diameter neurons. After treatment with inflammatory mediators, the resting membrane potential of Na1.9 KO neurons was slightly more negative than that of wild-type control neurons. This suggests that Na1.9 channels are active under this condition and therefore increases the ease with which action potentials are elicited after OxPL stimulation. In summary, our data suggest that Na1.9 has a switch function to potentiate the receptor potentials induced by OxPL under inflammatory conditions. Since human Na1.9 has been shown to mediate painful and painless channelopathies, this study provides new insights into the mechanism by which Na1.9 amplifies stimuli of endogenous irritants under inflammatory conditions.
PubMed: 29410612
DOI: 10.3389/fnmol.2018.00007 -
Current Neuropharmacology 2019The co-agonist concerted transition model is a simple and practical solution to analyze various aspects of GABAA receptor function. Several model-based predictions have... (Review)
Review
The co-agonist concerted transition model is a simple and practical solution to analyze various aspects of GABAA receptor function. Several model-based predictions have been verified experimentally in previous reports. We review here the practical implications of the model and demonstrate how it enables simplification of the experimental procedure and data analysis to characterize the effects of mutations or properties of novel ligands. Specifically, we show that the value of EC50 and the magnitude of current response are directly affected by basal activity, and that coapplication of a background agonist acting at a distinct site or use of a gain-of-function mutation can be employed to enable studies of weak activators or mutated receptors with impaired gating. We also show that the ability of one GABAergic agent to potentiate the activity elicited by another is a computable value that depends on the level of constitutive activity of the ion channel and the ability of each agonist to directly activate the receptor. Significantly, the model accurately accounts for situations where the paired agonists interact with the same site compared to distinct sites on the receptor.
Topics: Allosteric Regulation; GABA-A Receptor Agonists; Mutation; Propofol; Receptors, GABA-A
PubMed: 30520374
DOI: 10.2174/1570159X17666181206092418 -
Platelets Jul 2021Platelets have largely demonstrated their implication in anti-infectious immunity. This effect is ensured by the secreted molecules stored mostly in platelet alpha...
Platelets have largely demonstrated their implication in anti-infectious immunity. This effect is ensured by the secreted molecules stored mostly in platelet alpha granules. Previous studies have reported that showed sensitivity to this antibacterial effect of platelets. Statins, for their part, have shown a modulating effect on platelet activation. Furthermore, several studies have reported a protective effect of statins in staphylococcal endocarditis. The aim of this study was to investigate the influence of statins on the antibacterial effect of washed platelets. Blood samples were collected from healthy donors (n = 35). PRP was prepared according to the ISTH recommendation. Bacteria were incubated for four hours with untreated-washed platelets, or rather treated by statins and/or GPIIbIIIa antagonists. In order to evaluate the antibacterial effect, the platelet-bacteria mix was spread on the blood agar to count the number of colonies after 18 hours of incubation. Measurement of CD 41 and CD62P expression by flow cytometry was performed to evaluate the effect of statin on bacterial-induced platelet activation. Statins have shown a potentiation of the antibacterial effect of washed platelets ( < .01 for Atorvastatin and Rosuvastatin and < .001 for Fluvastatin untreated washed platelets condition). This effect of statins was dose-dependent and was more significant at 20 μM. The addition of Fluvastatin to platelet-bacterial mix significantly increased the expression of platelet CD41 and CD62P ( < .05 and < .01 vs resting washed platelets, respectively). Tirofiban, GPIIbIIIa antagonist, reversed the antibacterial effect of washed platelets and suppressed the potentiating effect of statins. Our study demonstrated that statins potentiate the anti-staphylococcal effect of washed platelets. This result may explain the beneficial effect of statins on infective endocarditis. Further studies are therefore required to explain this effect at the molecular level and to assess its impact .
Topics: Anti-Bacterial Agents; Blood Platelets; Healthy Volunteers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Staphylococcus aureus
PubMed: 32664773
DOI: 10.1080/09537104.2020.1792434 -
Current Opinion in Pulmonary Medicine Nov 2017Several new therapeutic modalities have recently become available to be used in patients with cystic fibrosis such as potentiators, modulators, and probiotics. Although... (Review)
Review
PURPOSE OF REVIEW
Several new therapeutic modalities have recently become available to be used in patients with cystic fibrosis such as potentiators, modulators, and probiotics. Although the effects on pulmonary function have been well documented, gastrointestinal outcomes have been addressed only rarely.
RECENT FINDINGS
Both the potentiator (ivacaftor) and the potentiator/modulator combination (ivacaftor/lumacaftor) that are currently on the market have a positive effect on BMI. Young patients (2-5 years of age) with a gating mutation may show improvement of exocrine pancreatic function on ivacaftor. In this specific patient population this agent also seems to improve intestinal pH and reflux. The effect of these medications on other gastrointestinal outcomes, such as intestinal inflammation and cystic fibrosis liver disease, has not been described so far. Furthermore, the results of several trials suggest that probiotics might reduce intestinal inflammation. Finally, organoids might be used to predict in vitro the clinical effect of potentiators and modulators.
SUMMARY
The effect of new interventions on the gastrointestinal outcomes studied so far is favourable. Future studies should address the effect on other gastrointestinal parameters.
Topics: Aminophenols; Aminopyridines; Benzodioxoles; Body Mass Index; Chloride Channel Agonists; Cystic Fibrosis; Digestive System; Drug Combinations; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Intestinal Diseases; Liver Diseases; Probiotics; Quinolones; Treatment Outcome; Weight Gain
PubMed: 28787381
DOI: 10.1097/MCP.0000000000000423 -
The Journal of Chemical Physics Dec 2022Neural network (NN) potentials are a natural choice for coarse-grained (CG) models. Their many-body capacity allows highly accurate approximations of the potential of...
Neural network (NN) potentials are a natural choice for coarse-grained (CG) models. Their many-body capacity allows highly accurate approximations of the potential of mean force, promising CG simulations of unprecedented accuracy. CG NN potentials trained bottom-up via force matching (FM), however, suffer from finite data effects: They rely on prior potentials for physically sound predictions outside the training data domain, and the corresponding free energy surface is sensitive to errors in the transition regions. The standard alternative to FM for classical potentials is relative entropy (RE) minimization, which has not yet been applied to NN potentials. In this work, we demonstrate, for benchmark problems of liquid water and alanine dipeptide, that RE training is more data efficient, due to accessing the CG distribution during training, resulting in improved free energy surfaces and reduced sensitivity to prior potentials. In addition, RE learns to correct time integration errors, allowing larger time steps in CG molecular dynamics simulation, while maintaining accuracy. Thus, our findings support the use of training objectives beyond FM, as a promising direction for improving CG NN potential's accuracy and reliability.
Topics: Entropy; Thermodynamics; Reproducibility of Results; Molecular Dynamics Simulation; Dipeptides
PubMed: 36586977
DOI: 10.1063/5.0124538