RESUMO
A novel antibiotic, CJ-15,801 (I), was isolated from the fermentation broth of a fungus, Seimatosporium sp. CL28611. The structure was determined to be a pantothenic acid analog having an alpha,beta-unsaturated carboxylic acid moiety by spectroscopic analyses. The compound inhibits the growth of multi-drug resistant (MDR) Staphylococcus aureus strains with MIC ranging from 6.25 to 50 microg/ml.
Assuntos
Antibacterianos/isolamento & purificação , Ácido Pantotênico/isolamento & purificação , Antibacterianos/química , Antibacterianos/farmacologia , Fermentação , Testes de Sensibilidade Microbiana , Ácido Pantotênico/análogos & derivados , Ácido Pantotênico/química , Ácido Pantotênico/farmacologiaRESUMO
Peptidic glucagon antagonists have been shown to lower blood glucose levels in diabetic models (1-3), but attempts to identify small molecular weight glucagon receptor-binding antagonists have met with little success. Skyrin, a fungal bisanthroquinone, exhibits functional glucagon antagonism by uncoupling the glucagon receptor from adenylate cyclase activation in rat liver membranes (1). We have examined the effects of skyrin on cells transfected with the human glucagon receptor and on isolated rat and human hepatocytes. The skyrin used was isolated from Talaromyces wortmanni American Type Culture Collection 10517. In rat hepatocytes, skyrin (30 micromol/l) inhibited glucagon-stimulated cAMP production (53%) and glucose output (IC50 56 micromol/l). There was no detectable effect on epinephrine or glucagon-like peptide 1 (GLP-1) stimulation of these parameters, which demonstrates skyrin's selective activity. Skyrin was also evaluated in primary cultures of human hepatocytes. Unlike cell lines, which are largely unresponsive to glucagon, primary human hepatocytes exhibited glucagon-dependent cAMP production for 14 days in culture (EC50 10 nmol/l). Skyrin (10 micromol/l) markedly reduced glucagon-stimulated cAMP production (55%) and glycogenolysis (27%) in human hepatocytes. The inhibition of glucagon stimulation was a specific property displayed by skyrin and oxyskyrin but not shared by other bisanthroquinones. Skyrin is the first small molecular weight nonpeptidic agent demonstrated to interfere with the coupling of glucagon to adenylate cyclase independent of binding to the glucagon receptor. The data presented in this study indicate that functional uncoupling of the human glucagon receptor from cAMP production results in metabolic effects that could reduce hepatocyte glucose production and hence alleviate diabetic hyperglycemia.
Assuntos
Antraquinonas/farmacologia , Glucagon/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Animais , Células CHO , Células Cultivadas , Cricetinae , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Epinefrina/farmacologia , Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon , Glucose/metabolismo , Glicogênio/metabolismo , Humanos , Masculino , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Glucagon/genética , TransfecçãoRESUMO
Among methods of controlling hypercholesterolemia and hyperlipidemia is the direct stimulation of hepatic low density lipoprotein (LDL) receptors. Two novel lactone compounds, CJ-12,950 and CJ-13,357, containing and unusual oxime moiety, were isolated from a zygomycete Mortierella verticillata. These lactones are potent inducers of the LDL receptor gene in vitro, that enhanced LDL receptor expression in human hepatocytes 2-fold at 100 nM.
Assuntos
Lactonas , Lactonas/química , Lactonas/isolamento & purificação , Mucorales/química , Receptores de LDL/genética , Técnicas de Cultura de Células , Fermentação , Regulação da Expressão Gênica , Humanos , Lactonas/farmacologia , Macrolídeos/química , Macrolídeos/isolamento & purificação , Macrolídeos/farmacologia , Mucorales/metabolismoRESUMO
Eight novel quinolones with anti-Helicobacter pylori activity were isolated from the actinomycete Pseudonocardia sp. CL38489. The quinolones were very potent against H. pylori with MICs up to 0.1 ng/ml. The quinolones appear to be specific for H. pylori, since they did not show antimicrobial activity when tested against a panel of other microorganisms.
Assuntos
Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Helicobacter pylori/efeitos dos fármacos , 4-Quinolonas , Actinomycetaceae , Anti-Infecciosos/química , Fermentação , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Seven new phthalide compounds with anti-Helicobacter pylori activities were isolated from the basidiomycete Phanerochaete velutina CL6387. The two most potent phthalide compounds, CJ-12,954 and CJ-13,014, have MICs of 5 ng/ml. The structure-activity relationship shows that the presence of a spiroketal part in addition to the phthalide part, greatly enhances the activity. The phthalide compounds appear to be specific for H. pylori, since they did not show antibacterial activities when tested against a panel of other microorganisms.
Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Basidiomycota/metabolismo , Helicobacter pylori/efeitos dos fármacos , Antibacterianos , Anti-Infecciosos/metabolismo , Basidiomycota/química , Benzofuranos/química , Benzofuranos/metabolismo , Benzofuranos/farmacologia , Fermentação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of expression plasmids was constructed to compare the usefulness of various promoters for the synthesis of a given protein in the Saccharomyces cerevisiae. The plasmids pMBL212, -213, -214, -215 and -216 can be used to synthesize the protein of interest directly as a non-fused protein or, if the protein is difficult to detect, indirectly as an enzymatically active beta-galactosidase fusion protein. The plasmids were employed to identify which yeast promoter and strain are suitable for the synthesis of poliovirus protein VP2. It was concluded that the GAL7 and PGK promoters in combination with strain X904 can be used for efficient synthesis of a VP2 in the form of a N-terminally fused VP2-beta-galactosidase protein.