RESUMO
Four tunicamycin class compounds, tunicamycin VII (1), tunicamycin VIII (2), corynetoxin U17a (3), and tunicamycin IX (4), were isolated from the culture broth of the marine-derived actinomycete Streptomyces sp. MBTG32. The strain was identified using the 16S rDNA sequencing technique, and the isolated strain was closely related to Streptomyces bacillaris. The structures of the isolated compounds were elucidated based on spectroscopic data and comparisons with previously reported NMR data. Compounds 1-4 showed potent antibacterial activities against Gram-positive bacteria, especially Staphylococcus aureus, with MIC values of 0.13-0.25 µg/mL. Through a recombinant enzyme assay and overexpression analysis, we found that the isolated compounds exerted potent inhibitory effects on S. aureus MurNAc-pentapeptide translocase (MraY), with IC50 values of 0.08-0.21 µg/mL. The present results support that the underlying mechanism of action of tunicamycins isolated from marine-derived Streptomyces sp. is also associated with the inhibition of MraY enzyme activity in S. aureus.
Assuntos
Antibacterianos , Proteínas de Bactérias , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Streptomyces , Tunicamicina , Staphylococcus aureus/efeitos dos fármacos , Tunicamicina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos) , Transferases/antagonistas & inibidores , Transferases/metabolismo , Organismos AquáticosRESUMO
Marinobazzanan (1), a new bazzanane-type sesquiterpenoid, was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was elucidated using NMR and mass spectroscopic data, while the relative configurations were established through the analysis of NOESY data. The absolute configurations of 1 were determined by the modified Mosher's method as well as vibrational circular dichroism (VCD) spectra calculation and it was determined as 6R, 7R, 9R, and 10R. It was found that compound 1 was not cytotoxic to human cancer cells, including A549 (lung cancer), AGS (gastric cancer), and Caco-2 (colorectal cancer) below the concentration of 25 µM. However, compound 1 was shown to significantly decrease cancer-cell migration and invasion and soft-agar colony-formation ability at concentrations ranging from 1 to 5 µM by downregulating the expression level of KITENIN and upregulating the expression level of KAI1. Compound 1 suppressed ß-catenin-mediated TOPFLASH activity and its downstream targets in AGS, A549, and Caco-2 and slightly suppressed the Notch signal pathway in three cancer cells. Furthermore, 1 also reduced the number of metastatic nodules in an intraperitoneal xenograft mouse model.
Assuntos
Antineoplásicos , Sesquiterpenos , Humanos , Animais , Camundongos , Células CACO-2 , Transformação Celular Neoplásica , Antineoplásicos/química , Movimento Celular , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Estrutura MolecularRESUMO
Background: Streptococcus mutans, an important Gram-positive pathogen in dental caries, uses sortase A (SrtA) to anchor surface proteins to the bacterial cell wall, thereby promoting biofilm formation and attachment to the tooth surface. Design: Based on activity-guided separation, inhibitors of S. mutans SrtA were isolated from Juniperus chinensis and identified through combined spectroscopic analysis. Further effects of isolated SrtA inhibitor on S. mutans were evaluated on bacterial aggregation, adherence and biofilm formation. Results: Six compounds (1-6) were isolated from the dried heartwood of J. chinensis. A novel compound designated 3',3"-dihydroxy-(-)-matairesinol (1) was identified, which exhibited potent inhibitory activity toward S. mutans SrtA (IC50 = 16.1 µM) without affecting microbial viability (minimum inhibitory concentration > 300 µM). The results of subsequent bioassays using compound 1 indicated that this compound inhibits S. mutans aggregation, adhesion and biofilm formation on solid surfaces by inhibiting SrtA activity. The onset and magnitude of inhibition of adherence and biofilm formation in S. mutans treated with compound 1 at 4× the SrtA IC50 are comparable to the behaviors of the untreated srtA-deletion mutant. Conclusion: Our findings suggest that small-molecule inhibitors of S. mutans SrtA may be useful for the prevention of dental plaque and treatment of dental microbial diseases.
RESUMO
Two new pyrrolosesquiterpenes, glaciapyrroles D (1) and E (2) were discovered along with the previously reported glaciapyrrole A (3) from Streptomyces sp. GGS53 strain isolated from deep-sea sediment. This study elucidated the planar structures of 1 and 2 using nuclear magnetic resonance (NMR), mass spectrometry (MS), ultraviolet (UV), and infrared (IR) spectroscopic data. The absolute configurations of the glaciapyrroles were determined by Mosher's method, circular dichroism spectroscopy, and X-ray crystallography. Under 366 nm UV irradiation, the glaciapyrroles were systematically converted to the corresponding photoglaciapyrroles (4-6) via photoisomerization, resulting in the diversification of the glaciapyrrole family compounds. The transformation of the glaciapyrrole Z to E isomers occurred in a 1:1 ratio, based on virtual validation of the photoisomerization of these olefinic compounds by 1H-NMR spectroscopy and liquid chromatography/mass spectrometry (LC/MS) analysis. Finally, when encapsulated in poly(lactic-co-glycolic acid) nanoparticles, glaciapyrrole E and photoglaciapyrrole E displayed significant inhibitory activity against influenza A virus. This is the first report of antiviral effects from glaciapyrrole family compounds, whose biological functions have only been subjected to limited studies so far.
Assuntos
Streptomyces , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Streptomyces/químicaRESUMO
A new nonribosomal peptide, nyuzenamide C (1), was discovered from riverine sediment-derived Streptomyces sp. DM14. Comprehensive analysis of the spectroscopic data of nyuzenamide C (1) revealed that 1 has a bicyclic backbone composed of six common amino acid residues (Asn, Leu, Pro, Gly, Val, and Thr) and four nonproteinogenic amino acid units, including hydroxyglycine, ß-hydroxyphenylalanine, p-hydroxyphenylglycine, and 3,ß-dihydroxytyrosine, along with 1,2-epoxypropyl cinnamic acid. The absolute configuration of 1 was proposed by J-based configuration analysis, the advanced Marfey's method, quantum mechanics-based DP4 calculations, and bioinformatic analysis of its nonribosomal peptide synthetase biosynthetic gene cluster. Nyuzenamide C (1) displayed antiangiogenic activity in human umbilical vein endothelial cells and induced quinone reductase in murine Hepa-1c1c7 cells.
Assuntos
Streptomyces , Aminoácidos/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Cinamatos , Células Endoteliais/metabolismo , Humanos , Camundongos , Fragmentos de Peptídeos , Peptídeos/química , Streptomyces/químicaRESUMO
Striae distensae (SD) or stretch marks are common linear scars of atrophic skin with disintegrating extracellular matrix (ECM) structures. Although fibroblasts contribute to the construction of ECM structure in SD, some studies have reported that mast cell degranulation causes the disruption of ECM in early SD lesions. Lagerstroemia indica flower (LIF) has traditionally been used in India as a diuretic. However, little is known about the effect and molecular action of Lagerstroemia indica flower extract (LIFE) on alleviating SD. This study evaluated the effects of LIFE on mast cell degranulation and the synthesis of ECM components in fibroblasts. LIFE inhibits the adhesion of rat basophilic leukemia (RBL) cells, RBL-2H3 on fibronectin (FN) and the expression of integrin, a receptor for FN, thereby reducing focal adhesion kinase (FAK) phosphorylation. In addition, LIFE attenuated the allergen-induced granules and cytokine interleukin 3 (IL-3) through the adhesion with FN. Moreover, the conditioned medium (CM) of activated mast cells decreases the synthesis of ECM components, and LIFE restores the abnormal expressions induced by activated mast cells. These results demonstrate that LIFE suppresses FN-induced mast cell activation and promotes the synthesis of ECM components in fibroblast, which indicates that LIFE may be a useful cosmetic agent for SD treatment.
Assuntos
Flores/química , Lagerstroemia/química , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Biomarcadores , Adesão Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Linhagem Celular , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Expressão Gênica , Imunoglobulina E/imunologia , Cadeias alfa de Integrinas/genética , Cadeias beta de Integrinas/genética , Fosforilação , Ligação Proteica/efeitos dos fármacos , Estrias de DistensãoRESUMO
Two nitrogenous metabolites, bacillimide (1) and bacillapyrrole (2), were isolated from the culture broth of the marine-derived actinomycete Streptomyces bacillaris. Based on the results of combined spectroscopic and chemical analyses, the structure of bacillimide (1) was determined to be a new cyclopenta[c]pyrrole-1,3-dione bearing a methylsulfide group, while the previously reported bacillapyrrole (2) was fully characterized for the first time as a pyrrole-carboxamide bearing an alkyl sulfoxide side chain. Bacillimide (1) and bacillapyrrole (2) exerted moderate (IC50 = 44.24 µM) and weak (IC50 = 190.45 µM) inhibitory effects on Candida albicans isocitrate lyase, respectively. Based on the growth phenotype using icl-deletion mutants and icl expression analyses, we determined that bacillimide (1) inhibits the transcriptional level of icl in C. albicans under C2-carbon-utilizing conditions.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Isocitrato Liase/efeitos dos fármacos , Streptomyces/metabolismo , Antifúngicos/isolamento & purificação , Candida albicans/enzimologia , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Nitrogênio/metabolismoRESUMO
Single-strain cultivation of a mountain soil-derived Streptomyces sp. GA02 and its coculture with Pandoraea sp. GA02N produced two aromatic products, gwanakosides A and B (1 and 2, respectively). Their spectroscopic analysis revealed that 1 is a new dichlorinated naphthalene glycoside and 2 is a pentacyclic aromatic glycoside. The assignment of the two chlorine atoms in 1 was confirmed by the analysis of its band-selective CLIP-HSQMBC spectrum. The sugars in the gwanakosides were identified as 6-deoxy-α-l-talopyranose based on 1H-1H coupling constants, Rotating frame Overhauser enhancement spectroscopy (ROESY) NMR correlations, and chemical derivatization followed by spectroscopic and chromatographic analyses. The absolute configuration of 2, whose production was enhanced approximately 100-fold in coculture, was proposed based on a quantum mechanics-based chemical shift analysis method, DP4 calculations, and the chemically determined configuration of 6-deoxy-α-l-talopyranose. Gwanakoside A displayed inhibitory activity against pathogenic bacteria, including Staphylococcus aureus (MIC = 8 µg/mL) and Mycobacterium tuberculosis (MIC50 = 15 µg/mL), and antiproliferative activity against several human cancer cell lines (IC50 = 5.6-19.4 µM).
Assuntos
Burkholderiaceae , Streptomyces , Humanos , Burkholderiaceae/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Ensaios de Seleção de Medicamentos Antitumorais , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Teoria Quântica , Espectrometria de Massas por Ionização por Electrospray , Staphylococcus aureus/efeitos dos fármacos , Streptomyces/metabolismoRESUMO
Ochraceopetalin (1), a mixed-biogenetic salt compound and its component 2 were isolated from the culture broths of a marine-derived fungus, Aspergillus ochraceopetaliformis. Based on combined spectroscopic and chemical analyses, the structure of 1 was determined to be a sulfonated diphenylether-aminol-amino acid ester guanidinium salt of an unprecedented structural class, while 2 was determined to be the corresponding sulfonated diphenylether. Ochraceopetaguanidine (3), the other guanidine-bearing aminol amino acid ester component, was also prepared and structurally elucidated. Compound 1 exhibited significant cytotoxicity against K562 and A549 cells.
Assuntos
Antineoplásicos/farmacologia , Aspergillus/química , Células A549/efeitos dos fármacos , Organismos Aquáticos , Humanos , Células K562/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The tropolone-bearing sesquiterpenes juniperone A (1) and norjuniperone A (2) were isolated from the folk medicinal plant Juniperus chinensis, and their structures were determined by a combination of spectroscopic and crystallographic methods. Photojuniperones A1 (3) and A2 (4), bearing bicyclo[3,2,0]heptadienones derived from tropolone, were photochemically produced and structurally identified by spectroscopic methods. Predicted by the machine learning-based assay, 1 significantly inhibited the action of tyrosinase. The new compounds also inhibited lipid accumulation and enhanced the extracellular glycerol excretion.
Assuntos
Juniperus/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Sesquiterpenos/farmacologia , Tropolona/farmacologia , Animais , Células Hep G2 , Humanos , Melanócitos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Fotoquímica , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , República da Coreia , Sesquiterpenos/isolamento & purificação , Tropolona/isolamento & purificação , Madeira/químicaRESUMO
Four epipolythiodioxopiperazine fungal metabolites (1-4) isolated from the sponge-derived Aspergillus quadrilineatus FJJ093 were evaluated for their capacity to inhibit isocitrate lyase (ICL) in the glyoxylate cycle of Candida albicans. The structures of these compounds were elucidated using spectroscopic techniques and comparisons with previously reported data. We found secoemestrin C (1) (an epitetrathiodioxopiperazine derivative) to be a potent ICL inhibitor, with an inhibitory concentration of 4.77 ± 0.08 µM. Phenotypic analyses of ICL-deletion mutants via growth assays with acetate as the sole carbon source demonstrated that secoemestrin C (1) inhibited C. albicans ICL. Semi-quantitative reverse-transcription polymerase chain reaction analyses indicated that secoemestrin C (1) inhibits ICL mRNA expression in C. albicans under C2-assimilating conditions.
Assuntos
Candida albicans/efeitos dos fármacos , Proteínas Fúngicas/antagonistas & inibidores , Isocitrato Liase/antagonistas & inibidores , Piperazinas/farmacologia , Aspergillus/metabolismo , Candida albicans/genética , Candida albicans/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Glioxilatos/metabolismo , Isocitrato Liase/química , Isocitrato Liase/genética , Piperazinas/química , Piperazinas/metabolismo , Proteínas Recombinantes/químicaRESUMO
Psammocindoles A-C (1-3), a new class of indole alkaloids, were isolated from a Psammocinia vermis sponge. By combined spectroscopic analyses, the structures of these compounds were determined to be the indole-γ-lactams derived from three amino acid residues. In addition, an enantiomer psammocindole D (4), and the N-lactam isomers isopsammocindoles A-D (5-8) were also synthesized. These natural products and synthetic analogues were found to significantly stimulate adiponectin secretion in human bone marrow mesenchymal stem cells.
Assuntos
Alcaloides Indólicos/química , Lactamas/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Poríferos/química , Animais , Produtos Biológicos , Humanos , Alcaloides Indólicos/isolamento & purificação , Lactamas/isolamento & purificação , Células-Tronco Mesenquimais/química , Estrutura Molecular , EstereoisomerismoRESUMO
Two new nonribosomal peptides, bonnevillamides D and E (1 and 2), have been discovered in Streptomyces sp. UTZ13 isolated from the carrion beetle, Nicrophorus concolor. Combinational analysis of the UV, MS, and NMR spectroscopic data revealed that their planar structures were comprised of dichlorinated linear peptides containing nonproteinogenic amino acid residues, such as 4-methylazetidinecarboxylic acid and 4-O-acetyl-5-methylproline. The configurations of bonnevillamides D and E (1 and 2) were determined based on ROESY correlations, the advanced Marfey's method, phenylglycine methyl ester derivatization, molecular modeling, and circular dichroism spectroscopy. The nonribosomal peptide synthetase biosynthetic pathway of bonnevillamides D and E has been proposed using bioinformatic analysis of the whole-genome sequence data of Streptomyces sp. UTZ13. Their biological activity toward the aggregation of amyloid-ß, which is one of the key pathogenic proteins in Alzheimer's disease, was evaluated using a thioflavin T assay and gel electrophoresis. Bonnevillamides D and E reversed the fibril formation by inducing the monomerization of amyloid-ß aggregates.
Assuntos
Actinobacteria , Azetidinas , Besouros , Streptomyces , Animais , PeptídeosRESUMO
Two new secondary metabolites, svalbamides A (1) and B (2), were isolated from a culture extract of Paenibacillus sp. SVB7 that was isolated from surface sediment from a core (HH17-1085) taken in the Svalbard archipelago in the Arctic Ocean. The combinational analysis of HR-MS and NMR spectroscopic data revealed the structures of 1 and 2 as being lipopeptides bearing 3-amino-2-pyrrolidinone, d-valine, and 3-hydroxy-8-methyldecanoic acid. The absolute configurations of the amino acid residues in svalbamides A and B were determined using the advanced Marfey's method, in which the hydrolysates of 1 and 2 were derivatized with l- and d- forms of 1-fluoro-2,4-dinitrophenyl-5-alanine amide (FDAA). The absolute configurations of 1 and 2 were completely assigned by deducing the stereochemistry of 3-hydroxy-8-methyldecanoic acid based on DP4 calculations. Svalbamides A and B induced quinone reductase activity in Hepa1c1c7 murine hepatoma cells, indicating that they represent chemotypes with a potential for functioning as chemopreventive agents.
Assuntos
Anticarcinógenos/farmacologia , Proteínas de Bactérias/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Lipopeptídeos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Paenibacillus/metabolismo , Animais , Anticarcinógenos/isolamento & purificação , Regiões Árticas , Proteínas de Bactérias/isolamento & purificação , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Ecossistema , Sedimentos Geológicos/microbiologia , Humanos , Lipopeptídeos/isolamento & purificação , Neoplasias Hepáticas/enzimologia , Camundongos , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Relação Estrutura-AtividadeRESUMO
Dumulmycin (1) was isolated from Streptomyces sp. DM28, a bacterial strain from a riverine sediment sample. The structure of 1 was elucidated as a bicyclic macrolide possessing 19-membered and 5-membered rings by spectroscopic analysis. The stereochemistry of 1 was determined by J-based configuration analysis, ROESY NMR data, DP4 calculations, and the modified Mosher's method. Genetic analysis identified a trans-acyltransferase polyketide biosynthetic gene cluster for 1. Dumulmycin exhibited in vitro antitubercular activity (MIC50 = 27.1 µM).
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Streptomyces/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Macrolídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Policetídeos/químicaRESUMO
BACKGROUND: Alzheimer's disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-ß (Aß) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aß or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aß and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together. OBJECTIVE: We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aß and tau aggregates through in vitro assessments. METHODS: We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aß fibrils. Then, anti-cytotoxic, anti-Aß, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis. RESULTS: When HT22 cells were exposed to Aß aggregates, the treatment of borrelidins alleviates the Aß-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aß aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aß aggregates but also directly regulates tau aggregation. CONCLUSION: Borrelidin dissociates insoluble Aß and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aß or anti-tau immunotherapy for clearance of both aggregates.
RESUMO
Disruptor of telomeric silencing-1 like (DOT1L) is a histone H3 methyltransferase which specifically catalyzes the methylation of histone H3 lysine-79 residue. Recent findings demonstrate that DOT1L is abnormally overexpressed and the upregulated DOT1L evokes the proliferation and metastasis in human breast cancer cells. Therefore, the DOT1L inhibitor is considered a promising strategy to treat breast cancers. Non-nucleoside DOT1L inhibitors, selenopsammaplin A and its analogues, were firstly reported in the present study. Selenopsammaplin A was newly designed and synthesized with 25% overall yield in 8 steps from 3-bromo-4-hydroxybenzaldahyde, and thirteen analogues of selenopsammaplin A were prepared for structure-activity relationship studies of their cytotoxicity against cancer cells and inhibitory activity toward DOT1L for antitumor potential. All synthetic selenopsammaplin A analogues exhibited the higher cytotoxicity compared to psammaplin A with up to 6 - 60 times depending on cancer cells, and most analogues showed significant inhibitory activities against DOT1L. Among the prepared analogues, the phenyl analogue (10) possessed the most potent activity with both cytotoxicity and inhibition of DOT1L. Compound 10 also exhibited the antitumor and antimetastatic activity in an orthotopic mouse metastasis model implanted with MDA-MB-231 human breast cancer cells. These biological findings suggest that analogue 10 is a promising candidate for development as a cancer chemotherapeutic agent in breast cancers.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-AtividadeRESUMO
Coprisamides C and D (1 and 2) were isolated from a gut bacterium, Micromonospora sp. UTJ3, of the carrion beetle Silpha perforata. Based on the combined analysis of UV, MS, and NMR spectral data, the planar structures of 1 and 2 were elucidated to be unreported derivatives of coprisamides A and B, cyclic depsipeptides bearing a 2-alkenylcinnamic acid unit and the unusual amino acids ß-methylaspartic acid and 2,3-diaminopropanoic acid. The absolute configuration of 1 was determined using the advanced Marfey's method, phenylglycine methyl ester derivatization, and J-based configuration analysis. The biosynthetic gene clusters for the coprisamides were investigated based on genomic data from coprisamide-producing strains Micromonospora sp. UTJ3 and Streptomyces sp. SNU533. Coprisamide C (1) was active against the Mycobacterium tuberculosis mc2 6230 strain.
Assuntos
Besouros/microbiologia , Depsipeptídeos/química , Microbioma Gastrointestinal , Micromonospora/química , Peptídeos Cíclicos/química , Animais , Vias Biossintéticas , Cinamatos , Depsipeptídeos/biossíntese , Testes de Sensibilidade Microbiana , Estrutura Molecular , Família Multigênica , Mycobacterium tuberculosis/efeitos dos fármacos , Peptídeos Cíclicos/biossíntese , República da Coreia , Metabolismo SecundárioRESUMO
Colorectal cancer (CRC) is a common and intractable malignancy with a high mortality risk. Conventional chemotherapeutics are effective for patients with early stage CRC, but the majority of deaths of CRC patients are linked to acquired drug resistance or metastasis occurrence. Asperphenin B (1), a lipopeptidyl benzophenone isolated from a marine-derived Aspergillus sp. fungus, reportedly possesses antiproliferative activity against cancer cells. However, its antitumor activity and the underlying molecular mechanisms remain unexplored. In this study, 1 induced G2/M phase cell cycle arrest and subsequent apoptotic cell death and inhibited tumor growth in a xenograft model. The 1-induced G2/M phase arrest was associated with the regulation of checkpoint proteins, including Chk1/2 and Cdc25c. The 1-induced apoptosis was correlated with an upregulation of p53 and cleaved caspases and a downregulation of survivin. Further experiments revealed that 1-mediated suppression of migration and invasion of metastatic HCT116 cells was partially associated with the downregulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. The antimetastatic potential of 1 was also confirmed by E-cadherin upregulation and N-cadherin and Snail downregulation, which were in turn associated with the GAPDH regulation. These findings highlight the potential use of 1 as a novel candidate for treating metastatic CRC with the modulation of GAPDH function.
Assuntos
Antineoplásicos/farmacologia , Aspergillus/química , Benzofenonas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Gliceraldeído-3-Fosfato Desidrogenases/antagonistas & inibidores , Animais , Antígenos CD , Apoptose/efeitos dos fármacos , Organismos Aquáticos/química , Caderinas , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This study aims to isolate and identify the structure of antibacterial compounds having potent activity on methicillin-resistant Staphylococcus aureus (MRSA) from marine actinomycetes, and also to identify their mode of action. Lactoquinomycin A (LQM-A) (compound 1) and its derivatives (2-4) were isolated from marine-derived Streptomyces bacillaris strain MBTC38, and their structures were determined using extensive spectroscopic methods. These compounds showed potent antibacterial activities against Gram-positive bacteria, with MIC values of 0.06-4 µg/mL. However, the tested compounds exhibited weak inhibitory activity against Gram-negative bacteria, although they were effective against Salmonella enterica (MIC = 0.03-1 µg/mL). LQM-A exhibited the most significant inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) (MIC = 0.25-0.5 µg/mL), with a low incidence of resistance. An in vivo dual-reporter assay designed to distinguish between compounds that inhibit translation and those that induce DNA damage was employed to assess the mode of action of LQM-A. LQM-A-induced DNA damage and did not inhibit protein synthesis. The gel mobility shift assay showed that LQM-A switched plasmid DNA from the supercoiled to relaxed form in a time- and concentration-dependent manner. These data suggest that LQM-A intercalated into double-stranded DNA and damaged DNA repair.