ABSTRACT
Research collaborations and licensing deals are critical for the discovery and development of life-saving drugs. This practice has been ongoing since the inception of the pharmaceutical industry. The current process of drug discovery and development is complex, regulated, and highly regimented, having evolved over time. Academia excels in the discovery of fundamental scientific concepts and biological processes, while industry excels in translational science and product development. Potential for collaboration exists at every step of the drug discovery and development continuum. This perspective walks through such collaborative activities, provides examples, and offers tips for potential collaborations.
Subject(s)
Drug Discovery , Drug Industry , Humans , History, 20th Century , Cooperative Behavior , History, 21st Century , Drug Development , AcademiaABSTRACT
Streptomyces platensis MA7327 is a bacterium producing interesting antibiotics, which act by the novel mechanism of inhibiting fatty acid biosynthesis. The antibiotics produced by this actinomycete are platensimycin and platencin plus some minor related antibiotics. Platensimycin and platencin have activity against antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; they also lack toxicity in animal models. Platensimycin also has activity against diabetes in a mouse model. We have been interested in studying the effects of primary metabolites on production of these antibiotics in our chemically defined production medium. In the present work, we tested 32 primary metabolites for their effect. They included 20 amino acids, 7 vitamins and 5 nucleic acid derivatives. Of these, only l-aspartic acid showed stimulation of antibiotic production. We conclude that the stimulatory effect of aspartic acid is due to its role as a precursor involved in the biosynthesis of aspartate-4-semialdehyde, which is the starting point for the biosynthesis of the 3-amino-2,4-dihydroxy benzoic acid portion of the platensimycin molecule.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Aspartic Acid/administration & dosage , Streptomyces/metabolism , Adamantane/isolation & purification , Amino Acids/administration & dosage , Amino Acids/metabolism , Aminobenzoates/isolation & purification , Aminophenols/isolation & purification , Anilides/isolation & purification , Anti-Bacterial Agents/biosynthesis , Aspartic Acid/chemistry , Nucleic Acids/administration & dosage , Nucleic Acids/metabolism , Polycyclic Compounds/isolation & purification , Vitamins/administration & dosage , Vitamins/metabolismABSTRACT
The actinomycete Streptomyces platensis produces two compounds that display antibacterial activity: platensimycin and platencin. These compounds were discovered by the Merck Research Laboratories, and a complex insoluble production medium was reported. We have used this medium as our starting point in our studies. In a previous study, we developed a semi-defined production medium, i.e., PM5. In the present studies, by varying the concentration of the components of PM5, we were able to develop a superior semi-defined medium, i.e., PM6, which contains a higher concentration of lactose. Versions of PM6, containing lower concentrations of all components, were also found to be superior to PM5. The new semi-defined production media contain dextrin, lactose, MOPS buffer, and ammonium sulfate in different concentrations. We determined antibiotic production capabilities using agar diffusion assays and chemical assays via thin-layer silica chromatography and high-performance liquid chromatography. We reduced crude nutrient carryover from the seed medium by washing the cells with distilled water. Using these semi-defined media, we determined that addition of the semi-defined component soluble starch stimulated antibiotic production and that it and dextrin could both be replaced with glucose, resulting in the chemically defined medium, PM7.
Subject(s)
Adamantane/metabolism , Aminobenzoates/metabolism , Anilides/metabolism , Anti-Bacterial Agents/metabolism , Culture Media/chemistry , Streptomyces/growth & development , Streptomyces/metabolism , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Microbial Sensitivity TestsABSTRACT
Platensimycin and platencin are compounds that were discovered at Merck Research Laboratories and have shown promising antibacterial activity. They are both produced in fermentation by the actinomycete Streptomyces platensis. Merck reported a crude, insoluble production medium to produce the antibiotics. To test the possible effects of different primary metabolites and inorganic compounds on the production of these antibiotics, a chemically-defined medium is needed. The effects that these compounds have on production could provide information about the precursors and biosynthetic pathway of the antibiotics. We have tested and developed a number of media with varying degrees of chemical definition and solubility using the Merck medium as our starting point. Our latest production medium, PM5, is soluble and semi-defined. It yields suitable production of the compounds, as shown by agar diffusion assays, bioautography and HPLC. The antibiotics were located in the extracellular broths and not in the mycelia.
Subject(s)
Adamantane/chemical synthesis , Aminobenzoates/chemical synthesis , Aminophenols/chemical synthesis , Anilides/chemical synthesis , Anti-Bacterial Agents/biosynthesis , Culture Media , Polycyclic Compounds/chemical synthesis , Streptomyces/metabolism , Adamantane/pharmacology , Aminobenzoates/pharmacology , Aminophenols/pharmacology , Anilides/pharmacology , Anti-Bacterial Agents/pharmacology , Fermentation , Polycyclic Compounds/pharmacologyABSTRACT
Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure-activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay. The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature.
Subject(s)
Aristolochic Acids/chemical synthesis , CDC2 Protein Kinase/antagonists & inhibitors , Pyrazoles/chemical synthesis , Quinolines/chemical synthesis , Aristolochic Acids/chemistry , Aristolochic Acids/pharmacology , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
The 70% aqueous methanolic extract of the Chinese plant Aristolochia manshuriensis was found to contain two novel substituted phenanthrene compounds, SCH 546909 (1), and another phenanthrene glycoside (2). The structures of 1 and 2 were established based on NMR studies. They were identified as inhibitors of the CDK2 enzyme. Compound 1 was found to be a potent inhibitor of the CDK2 enzyme with an IC50 of 140 nM, whereas compound 2 was found to be less active with an IC50 of >10 microM.
Subject(s)
Antineoplastic Agents/pharmacology , Aristolochia/chemistry , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Glycosides/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Plant Extracts/chemistry , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Enzyme Activation/drug effects , Glycosides/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Methanol/chemistry , Molecular Structure , Water/chemistrySubject(s)
Anti-Bacterial Agents/chemistry , Aspergillus/chemistry , Benzopyrans/chemistry , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/biosynthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Benzopyrans/pharmacology , Candida albicans/drug effects , Fermentation , Magnetic Resonance Spectroscopy , Molecular Conformation , Saccharomyces cerevisiae/drug effects , Staphylococcus aureus/drug effectsABSTRACT
Four new caryophyllene derivatives, Sch 725432 (1), Sch 601253 (2), Sch 601254 (3), and Sch 725434 (4), were isolated from the fungal fermentation broth of Chrysosporium pilosum by reversed-phase HPLC purification. The structure elucidation of trioxygenated caryophyllenes 1-4 was accomplished on the basis of spectroscopic data interpretation. Sch 725434 (4) possesses a dihydrofuran-3-one ring, forming a tricyclic ring skeleton, which represents an unprecedented ring skeleton for the caryophyllene-type of sesquiterpenes. Compounds 1-4 were evaluated for their antifungal activity.
Subject(s)
Chrysosporium/chemistry , Saccharomyces cerevisiae/drug effects , Sesquiterpenes/isolation & purification , Antifungal Agents/chemistry , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Polycyclic Sesquiterpenes , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacologyABSTRACT
Investigation of unexpected levels of impurities in Intron product has revealed the presence of low levels of impurities leached from the silicone tubing (Rehau RAU-SIK) on the Bosch filling line. In order to investigate the effect of these compounds (1a, 1b and 2) on humans, they were isolated identified and synthesized. They were extracted from the tubing by stirring in Intron placebo at room temperature for 72 h and were enriched on a reverse phase CHP-20P column, eluting with gradient aqueous ACN and were separated by HPLC. Structural elucidation of 1a, 1b and 2 by MS and NMR studies demonstrated them to be halogenated biphenyl carboxylic acids. The structures were confirmed by independent synthesis. Levels of extractable impurities in first filled vials of actual production are estimated to be in the range of 0.01-0.55 microg/vial for each leached impurity. Potential toxicity of these extractables does not represent a risk for patients under the conditions of clinical use.
Subject(s)
Drug Contamination , Interferon-alpha/chemistry , Interferon-alpha/isolation & purification , Organic Chemicals/chemistry , Silicones/chemistry , Buffers , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid/methods , Freeze Drying , Humans , Hydrogen-Ion Concentration , Interferon alpha-2 , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Molecular Structure , Powders , Quality Control , Recombinant Proteins , Temperature , Time FactorsABSTRACT
A novel fungal secondary metabolite, Sch 213766 was isolated from the fungal fermentation broth of Chaetomium globosum as the chemokine receptor CCR-5 inhibitor and shown to be the methyl ester of the previously described tetramic acid Sch 210972 on the basis of UV, MS and NMR spectral data analyses. Sch213766 exhibited an IC(50) value of 8.6 muM in the CCR-5 receptor in vitro binding assay.
Subject(s)
CCR5 Receptor Antagonists , Chaetomium/metabolism , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Anti-HIV Agents/metabolism , Chaetomium/growth & development , Culture Media, Conditioned/metabolism , Fermentation , Methyl Ethers/chemistry , Methyl Ethers/isolation & purification , Methyl Ethers/metabolism , Methyl Ethers/pharmacologyABSTRACT
Bioassay-guided fractionation of an active fraction from an extract of a marine starfish, Novodinia antillensis, led to the isolation and identification of two new saponins, Sch 725737 (1) and Sch 725739 (2). Compound 1 was identified as the NaV1.8 inhibitor with IC(50) of approximately 9 microM. The purification and the structure elucidation of these two saponins are described.
Subject(s)
Saponins/chemistry , Starfish/chemistry , Steroids/chemistry , Animals , Carbohydrate Sequence , Magnetic Resonance Spectroscopy , Membrane Potentials/drug effects , Saponins/isolation & purification , Saponins/pharmacology , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/isolation & purification , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Steroids/isolation & purification , Steroids/pharmacologyABSTRACT
Two novel chemokine receptor CCR-5 inhibitors, Sch 210971 (1) and Sch 210972 (2), were isolated from the fungal fermentation broth of Chaetomium globosum by normal- and reversed-phase HPLC purifications. The structure determination of 1 and 2 was accomplished on the basis of UV, MS, and NMR spectral data analyses including COSY, NOESY, HMQC, and HMBC experiments. The structure and relative configuration of 2 were determined unequivocally by X-ray crystallographic analysis. The major component 2 demonstrated a potent inhibitory activity of IC(50) = 79 nM in the CCR-5 receptor in vitro binding assay.
Subject(s)
Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Chaetomium/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Arizona , Crystallography, X-Ray , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Humans , Inhibitory Concentration 50 , Molecular Structure , Plant Leaves/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
A new 5-alkenylresorcinol Sch725681 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 16 and 64 microg/ml, respectively.
Subject(s)
Antifungal Agents/isolation & purification , Aspergillus/metabolism , Resorcinols/isolation & purification , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida albicans/drug effects , Magnetic Resonance Spectroscopy , Resorcinols/chemistry , Resorcinols/pharmacology , Saccharomyces cerevisiae/drug effectsABSTRACT
Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.
Subject(s)
Bacteria/metabolism , Biological Products/biosynthesis , Biological Products/chemistry , Drug Evaluation, Preclinical/methods , Pharmaceutical Preparations/isolation & purification , Animals , Bacteria/genetics , Biological Products/genetics , Pharmaceutical Preparations/chemistryABSTRACT
A new hydrogenated azaphilone Sch725680 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was achieved based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 64 microg/ml, respectively.
Subject(s)
Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Aspergillus/chemistry , Benzopyrans/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Aspergillus/metabolism , Benzopyrans/isolation & purification , Benzopyrans/pharmacology , Candida albicans/drug effects , Fermentation , Microbial Sensitivity Tests , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Saccharomyces cerevisiae/drug effects , Spectrometry, Mass, Electrospray Ionization , Staphylococcus aureus/drug effectsABSTRACT
The 70% aqueous methanolic extract of the Peruvian plant Oryctanthus sp. was found to contain a novel saccharide of a diene alpha,omega-diacid. Compound 1 was identified as an inhibitor of the VEGF receptor. The structure of this compound was established based on NMR studies. Compound 1 inhibited ligand binding to the VEGF receptor with an IC50 of 5.0 microM.
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Magnolia/chemistry , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Antineoplastic Agents/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Structure , Receptors, Vascular Endothelial Growth Factor/metabolismABSTRACT
A new microbial metabolite Sch 725424 (1) was isolated from the culture of Kitasatospora sp. The structure elucidation of 1 was accomplished based on NMR spectroscopic analyses as well as extensive structure elucidation of its dehydration product Sch 725428 (2). Compound 1 showed inhibitory activity against Staphylococcus aureus with MIC values 1-2 microg/ml, and also displayed weak antifungal activity against Saccharomyces cerevisiae (PM503) with an MIC 32 microg/ml.
Subject(s)
Amides/chemistry , Amides/metabolism , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/chemistry , Furans/chemistry , Furans/metabolism , Polyenes/chemistry , Polyenes/metabolism , Streptomycetaceae/metabolism , Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/metabolism , Antifungal Agents/pharmacology , Fermentation , Furans/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Polyenes/pharmacology , Saccharomyces cerevisiae/drug effects , Staphylococcus aureus/drug effectsABSTRACT
In recent years, large pharmaceutical companies have significantly reduced or eliminated the search for new therapeutic agents from natural sources. In spite of the many successes from natural product drug discovery, these companies have chosen to focus on compound libraries as the source of new lead compounds. Smaller biotechnology companies are continuing the search for novel natural products by developing and employing new and innovative approaches. This paper will describe some of these recent approaches to natural product drug discovery.:
Subject(s)
Anthracyclines , Anti-Bacterial Agents , Antifungal Agents , Micromonospora/metabolism , Anthracyclines/chemistry , Anthracyclines/isolation & purification , Anthracyclines/pharmacology , Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Fungi/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Microbial Sensitivity TestsABSTRACT
The 70% aqueous methanol extract of the Peruvian plant Lippia alva (Verbenaceae) was found to contain three novel compounds, 1, 2, and 3, which were identified as inhibitors of the chemokine receptor CCR5. The structures of 1-3 were established based on extensive NMR studies. Compounds 1-3 inhibited CCR5 receptor signaling as measured by a calcium mobilization assay with IC(50) values of 5.5, 6.0, and 7.2 microg/mL, respectively.