RESUMEN
Multidrug-resistant Staphylococcus aureus is one of the most clinically important pathogens in the world, with infections leading to high rates of morbidity and mortality in both humans and animals. The ability of S. aureus to form biofilms protects cells from antibiotics and promotes the transfer of antibiotic resistance genes; therefore, new strategies aimed at inhibiting biofilm growth are urgently needed. Probiotic species, including Bacillus subtilis, are gaining interest as potential therapies against S. aureus for their ability to reduce S. aureus colonization and virulence. Here, we search for strains and microbially derived compounds with strong antibiofilm activity against multidrug-resistant S. aureus by isolating and screening Bacillus strains from a variety of agricultural environments. From a total of 1,123 environmental isolates, we identify a single strain B. subtilis 6D1, with a potent ability to inhibit biofilm growth, disassemble mature biofilm, and improve antibiotic sensitivity of S. aureus biofilms through an Agr quorum sensing interference mechanism. Biochemical and molecular networking analysis of an active organic fraction revealed multiple surfactin isoforms, and an uncharacterized peptide was driving this antibiofilm activity. Compared with commercial high-performance liquid chromatography grade surfactin obtained from B. subtilis, we show these B. subtilis 6D1 peptides are significantly better at inhibiting biofilm formation in all four S. aureus Agr backgrounds and preventing S. aureus-induced cytotoxicity when applied to HT29 human intestinal cells. Our study illustrates the potential of exploring microbial strain diversity to discover novel antibiofilm agents that may help combat multidrug-resistant S. aureus infections and enhance antibiotic efficacy in clinical and veterinary settings. IMPORTANCE: The formation of biofilms by multidrug-resistant bacterial pathogens, such as Staphylococcus aureus, increases these microorganisms' virulence and decreases the efficacy of common antibiotic regimens. Probiotics possess a variety of strain-specific strategies to reduce biofilm formation in competing organisms; however, the mechanisms and compounds responsible for these phenomena often go uncharacterized. In this study, we identified a mixture of small probiotic-derived peptides capable of Agr quorum sensing interference as one of the mechanisms driving antibiofilm activity against S. aureus. This collection of peptides also improved antibiotic killing and protected human gut epithelial cells from S. aureus-induced toxicity by stimulating an adaptive cytokine response. We conclude that purposeful strain screening and selection efforts can be used to identify unique probiotic strains that possess specially desired mechanisms of action. This information can be used to further improve our understanding of the ways in which probiotic and probiotic-derived compounds can be applied to prevent bacterial infections or improve bacterial sensitivity to antibiotics in clinical and agricultural settings.
Asunto(s)
Antibacterianos , Bacillus subtilis , Biopelículas , Percepción de Quorum , Biopelículas/efectos de los fármacos , Percepción de Quorum/efectos de los fármacos , Bacillus subtilis/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Humanos , Péptidos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiologíaRESUMEN
Three new neolignan glycosides (1-3), a new phenolic glycoside (15), and a new cyanoglycoside (16) were isolated and characterized from the twigs of Aleurites fordii together with 14 known analogues (4-14 and 17-19). The structural elucidation of the new compounds was performed through the analysis of their NMR, HRMS, and ECD spectra and by chemical methods. All isolated compounds were tested for their antineuroinflammatory and neuroprotective activities.
RESUMEN
Three new oleanane-type triterpenoidal glycosides, imbalosides A-C (1-3), were isolated from the white flowers of Impatiens balsamina. The structures of these phytochemical constituents (1-3) were elucidated through 1D and 2D Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) data analyses followed by chemical methods. All the characterized compounds (1-3) were evaluated for their antiproliferative activity against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and BT549) and their anti-neuroinflammatory activity on the basis of inhibition levels of nitric oxide (NO) in the lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cell lines.
RESUMEN
Two new secoiridoid glycosides, obtusifolisides A and B (1, 2), together with 7 known secoiridoid glycosides (3-9) were isolated from the twigs of Ligustrum obtusifolium. The chemical structures of new compounds were determined by a spectroscopic data analysis, including one and two dimensional (1D-, 2D)-NMR, High resolution-MS, and experiments involving chemical reactions. The isolated secoiridoid glycosides were evaluated for their anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated BV-2 murine microglia cells. Compounds 2, 5, 6, 8, and 9 significantly reduced the production of nitric oxide (NO), with IC50 values of 5.45, 11.17, 14.62, 15.45, and 14.96 µM, respectively. None of the compounds were toxic to the cells. Additionally, we evaluated the neuroprotective effects of compounds 1-9 on nerve growth factor (NGF) induction in a C6 rat glioma cell line. Compounds 2 and 6 upregulated NGF secretion to 155.56±7.16%, and 139.35±11.65%, respectively, without significant cell toxicity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Glicósidos Iridoides/farmacología , Ligustrum/química , Fármacos Neuroprotectores/farmacología , Tallos de la Planta/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glioma/tratamiento farmacológico , Glioma/metabolismo , Glicósidos Iridoides/química , Glicósidos Iridoides/aislamiento & purificación , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Conformación Molecular , Factores de Crecimiento Nervioso/antagonistas & inhibidores , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Ratas , Relación Estructura-ActividadRESUMEN
Six new iridoid glycosides, sambucusides A-F (1-6), and two known derivatives (7 and 8) were isolated from a methanol extract of the twigs of Sambucus williamsii var. coreana. Their chemical structures were elucidated by spectroscopic methods, including NMR (1H and 13C NMR, 1H-1H COSY, HMQC, HMBC, and NOESY) and HRMS. All isolated compounds (1-8) were evaluated for their antiproliferative activities against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and Bt549). Their effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV-2 cells and their neuroprotective effects through induction of nerve growth factor (NGF) in C6 glioma cells were also examined. Compounds 2, 3, and 5 showed cytotoxic effects (IC50 1.3-8.7 µM) against the SK-MEL-2 and Bt549 cell lines and inhibitory effects on NO production (IC50 of 0.9, 1.3, and 1.2 µM, respectively). Compounds 2, 4, and 8 exhibited NGF-releasing effects (147.0 ± 5.8%, 158.7 ± 5.2%, and 152.6 ± 7.3%, respectively).
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Glicósidos Iridoides/aislamiento & purificación , Glicósidos Iridoides/farmacología , Lipopolisacáridos/farmacología , Factor de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/metabolismo , Óxido Nítrico/análisis , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Glicósidos Iridoides/química , Lipopolisacáridos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Factor de Crecimiento Nervioso/química , Fármacos Neuroprotectores/química , SambucusRESUMEN
A new sesquilignan glycoside 1, together with seven known phenolic glycosides 2-8 were isolated from the aerial parts of Capsella bursa-pastoris. The chemical structure of the new compound 1 was elucidated by extensive nuclear magnetic resonance (NMR) data (¹H- and 13C-NMR, ¹H-¹H correlation spectroscopy (¹H-¹H COSY), heteronuclear single-quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), and nuclear overhauser effect spectroscopy (NOESY)) and HR-FABMS analysis. The anti-inflammatory effects of 1-8 were evaluated in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Compounds 4 and 7 exhibited moderate inhibitory effects on nitric oxide production in LPS-activated BV-2 cells, with IC50 values of 17.80 and 27.91 µM, respectively.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Capsella/química , Glicósidos/química , Glicósidos/farmacología , Animales , Línea Celular , Supervivencia Celular , Glicósidos/aislamiento & purificación , Concentración 50 Inhibidora , Lipopolisacáridos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Óxido Nítrico/metabolismo , Fenoles/química , Extractos Vegetales/químicaRESUMEN
In our continuing search for bioactive constituents of Korean medicinal sources, we investigated an 80% MeOH extract of the twigs of Chaenomeles speciosa. Column chromatographic purification of the CHCl3 fraction resulted in the isolation of a new biphenyl derivative (1), along with four known biphenyl compounds (2-5) and six triterpenes (6-11). The chemical structure of the new compound was determined on the basis of spectroscopic analyses including 1D and 2D NMR data. Among isolates, compound 3 exhibited potent cytotoxic activities against SK-OV-3, SK-MEL-2, and XF498 cell lines (IC50=5.91, 4.22, and 6.28µM, respectively). Also, Compounds 9 and 10 showed strong anti-neuroinflammatory activities (IC50 2.38, and 6.70µM, respectively).
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Extractos Vegetales/farmacología , Rosaceae/química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Compuestos de Bifenilo/química , Compuestos de Bifenilo/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Tallos de la Planta/química , Relación Estructura-ActividadRESUMEN
Phytochemical investigation of the twigs of Syringa oblata var. diatata led to the isolation of two new secoiridoid glucosides, dilatioside A-B (1-2), along with thirteen known ones (3-15). The structures were determined by spectroscopic methods including one and two dimensional (1- and 2D-) NMR techniques, high resolution (HR)-FAB-MS, and chemical methods. The isolated compounds (1-15) were tested for the induction of nerve growth factor (NGF) secretion in a C6 rat glioma cell line and their cytotoxicity against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, HCT15) in vitro using a sulforhodamine B bioassay. Compounds 5, 7, 8, 10, and 14 were found to induce upregulation of NGF secretion without causing significant cell toxicity.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Glucósidos Iridoides/farmacología , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Syringa/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Glucósidos Iridoides/química , Glucósidos Iridoides/aislamiento & purificación , Conformación Molecular , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Tallos de la Planta/química , Ratas , Relación Estructura-ActividadRESUMEN
Four biflavonoid glycosides, balsamisides A-D (1-4), and nine known compounds (5-13) were obtained from the white petals of Impatiens balsamina. The 2D structures of the purified phytochemicals were established using conventional NMR techniques in addition to the new long-range HSQMBC NMR experiment. Acid hydrolysis followed by experimental and quantum-mechanics-based ECD data analysis permitted full configurational assignment of the purified metabolites. Compounds 1-13 were assessed for their potential to impede the generation of nitric oxide in lipopolysaccharide-stimulated BV2 cells. They were also investigated for potential neuroprotective activity using C6 cells and cytotoxicity against some human tumor cell lines, but were inactive (IC50 > 10 µM) against all the cell lines.
Asunto(s)
Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Biflavonoides/aislamiento & purificación , Biflavonoides/farmacología , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , Impatiens/química , Fármacos Neuroprotectores/aislamiento & purificación , Fármacos Neuroprotectores/farmacología , Algoritmos , Animales , Antiinflamatorios no Esteroideos/química , Biflavonoides/química , Glicósidos/química , Humanos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Fármacos Neuroprotectores/química , Óxido Nítrico/biosíntesis , Resonancia Magnética Nuclear Biomolecular , República de CoreaRESUMEN
A new pregnane-type steroidal glycoside (1), two new spirostane-type steroidal glycosides (2, 3), and two new furostane-type steroidal glycosides (4, 5), named allimacrosides A-E, together with four known compounds (6-9) were isolated from a 80% MeOH extract of Allium macrostemon Bunge. The identification and structural elucidation of these compounds were based on their 1D- and 2D-NMR spectra, and HR-FAB-MS data analysis. The isolated compounds were tested for cytotoxicity against four human tumor cell lines in vitro using the sulforhodamine B bioassay.
Asunto(s)
Allium/química , Glicósidos/química , Esteroides/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glicósidos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Rodaminas/química , Rodaminas/farmacologíaRESUMEN
Phytochemical investigation of the bark from the stems of Sorbus commixta led to the isolation and characterization of a new fatty acid, sorcomic acid (1), along with nine known analogues (2-10). The structure of the new compound (1) was determined through NMR ((1)H and (13)C NMR, HSQC, HMBC, and NOESY), MS, and specific optical rotation. The known compounds (2-10) were identified by comparison of their spectroscopic data with those in the literature. The biological activities of all the isolated compounds (1-10) were evaluated: compounds 1, 5, and 7 potently induced NGF secretion from C6 glioma cells (233.40 ± 12.82, 194.40 ± 8.05, and 185.74 ± 10.25 %, respectively) and compound 10 reduced NO levels with an IC50 value of 71.25 µM in murine microglia BV2 cells stimulated by LPS.
Asunto(s)
Ácidos Grasos/farmacología , Factor de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Sorbus/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ácidos Grasos/análisis , Ácidos Grasos/química , Estructura Molecular , Fármacos Neuroprotectores/análisis , Fármacos Neuroprotectores/química , Óxido Nítrico/metabolismo , Corteza de la Planta/química , Extractos Vegetales/química , RatasRESUMEN
As part of our ongoing search for bioactive constituents of natural Korean medicinal plants, three new lignan derivatives, sambucasinol A-C (1-3), together with 7 known compounds (4-10) were isolated from the twigs of Sambucus williamsii. The structures of these new compounds were determined by a combination of 1D and 2D NMR spectroscopic data analysis, as well as circular dichroism (CD) spectroscopy studies. Here, we evaluated the anti-inflammatory effects of 1-10 in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Compounds 1-3 exhibited significant inhibitory effects on nitric oxide production in LPS-activated BV-2 cells, with IC50 values of 6.82, 7.04, and 14.70 µM, respectively. Additionally, we evaluated the effects of compounds 1-10 on NGF induction in a C6 rat glioma cell line. Compounds 1-3 upregulated NGF secretion to 183.95 ± 2.63%, 153.99 ± 5.15%, and 155.96 ± 5.15%, respectively, without any significant cell toxicity. Moreover, all isolates were evaluated for their cytotoxicity against A549, SK-OV-3, SK-MEL-2, and XF498 cell lines. Compounds 1-3 showed consistent cytotoxicity against the four human cell lines, with IC50 values in the range of 11.07-19.62 µM.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos Fitogénicos/farmacología , Lignanos/farmacología , Sambucus/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lignanos/química , Lignanos/aislamiento & purificación , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Conformación Molecular , Factores de Crecimiento Nervioso/metabolismo , Tallos de la Planta/química , Ratas , Relación Estructura-ActividadRESUMEN
The CHCl3 soluble fraction of the 80% MeOH extract of the stems of Firmiana simplex strongly inhibited nitric oxide production in lipopolysaccharide-activated BV-2 cells. A bioactivity-guided column chromatographic separation yielded two new lignans, firmianols A and B (1-2) together with seventeen known lignans (3-19). The structural elucidation of the new compounds was determined by spectroscopic methods, including 1D, 2D NMR and HR-FAB-MS. All isolated lignans were evaluated for their antineuroinflammatory effects on nitric oxide (NO) production in lipopolysaccharides (LPS)-activated murine microglia BV2 cells. Among the isolated, compounds 14 and 15 showed potent inhibitory activity against NO production (IC50 1.05 and 0.929 µM, respectively) without cell toxicity in murine microglia BV-2 cells. Compounds 11-13 and 17 also exhibited strong inhibitory effects on NO production, with IC50 values ranging from 7.07 to 15.28 µM.
Asunto(s)
Antiinflamatorios/química , Lignanos/química , Malvaceae/química , Extractos Vegetales/química , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Concentración 50 Inhibidora , Lignanos/aislamiento & purificación , Lignanos/farmacología , Lipopolisacáridos/toxicidad , Espectroscopía de Resonancia Magnética , Malvaceae/metabolismo , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Conformación Molecular , Óxido Nítrico/metabolismo , Tallos de la Planta/química , Tallos de la Planta/genéticaRESUMEN
The phytochemical investigation of the methanol extract from the twigs of Spiraea prunifolia var. simpliciflora (Rosaceae) using column chromatography led to the isolation of a new phenol glycoside, 1-O-(E)-caffeoyl-2-O-p-(E)-coumaroyl-ß-D-glucopyranose (1), together with 16 known phenolic compounds (2-17). The structure of this new compound was elucidated by analysis of spectroscopic data including 1D, 2D nuclear magnetic resonance and HR-FAB-MS data. The isolated compounds were tested for cytotoxicity against four human tumor cell lines in vitro using the sulforhodamine B bioassay.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Glicósidos/farmacología , Fenoles/farmacología , Spiraea/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Cromatografía en Capa Delgada , Glicósidos/aislamiento & purificación , Humanos , Espectroscopía de Resonancia Magnética , Metanol/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fenoles/aislamiento & purificación , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
A phytochemical investigation of Allium tuberosum Rottler afforded two new phenylpropane glycosides, named tuberonoid A (1) and B (2), along with four known flavonoids, kaempferol 3-O-ß-sophoroside (3), 3-O-ß-D-(2-O-feruloyl)-glucosyl-7,4'-di-O-ß-D-glucosylkaempferol (4), 3-O-ß-sophorosyl-7-O-ß-D-(2-O-feruloyl)glucosyl kaempferol (5), kaempferol 3,4'-di-O-ß-D-glucoside (6). The identification and structural elucidation of the new compounds were carried out based on spectral data analyses ((1)H and (13)C NMR, (1)H-(1)H COSY, HMQC) and HR-MS.
Asunto(s)
Cebollino/química , Flavonoides/química , Glicósidos/química , Componentes Aéreos de las Plantas/química , Propano/análogos & derivados , Propano/química , Flavonoides/aislamiento & purificación , Glicósidos/aislamiento & purificación , Estructura Molecular , Propano/aislamiento & purificaciónRESUMEN
A bioassay-guided fractionation and chemical investigation of the MeOH extract from the twigs of Lindera glauca (SIEB. et ZUCC.) BLUME resulted in the isolation and identification of six lignans (1-6) including three new lignan derivatives, named linderuca A (1), B (2), and C (3). The structures of the new compounds (1-3) were determined on the basis of spectroscopic analyses, including two dimensional NMR and circular dichroism (CD) spectroscopy studies. The cytotoxic activities of the isolates (1-6) were evaluated by determining their inhibitory effects on human tumor cell lines. Compounds 1-5 showed antiproliferative activities against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines with IC50 values of 7.79-29.42 µM. Based on the understanding that inflammation is a crucial cause of tumor progression, we also investigated the anti-inflammatory activities of the isolates (1-6) in the lipopolysaccharide-stimulated murine microglia BV-2 cell line by measuring nitric oxide (NO) levels. The new lignans (1-3) significantly inhibited NO production with IC50 values of 12.10, 9.48, and 9.87 µM, respectively, without cytotoxicity.