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1.
Molecules ; 25(3)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033190

RESUMO

Abstract: A main cellular functional module that becomes dysfunctional during aging is the proteostasis network. In the present study, we show that benzoic acid derivatives isolated from Bjerkandera adusta promote the activity of the two main protein degradation systems, namely the ubiquitin-proteasome (UPP) and especially the autophagy-lysosome pathway (ALP) in human foreskin fibroblasts. Our findings were further supported by in silico studies, where all compounds were found to be putative binders of both cathepsins B and L. Among them, compound 3 (3-chloro-4-methoxybenzoic acid) showed the most potent interaction with both enzymes, which justifies the strong activation of cathepsins B and L (467.3 ± 3.9%) on cell-based assays. Considering that the activity of both the UPP and ALP pathways decreases with aging, our results suggest that the hydroxybenzoic acid scaffold could be considered as a promising candidate for the development of novel modulators of the proteostasis network, and likely of anti-aging agents.

2.
Bioorg Med Chem Lett ; 30(6): 126952, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32005414

RESUMO

In the course of a primary screening of 614 microbial actinomycete extracts for the discovery of tyrosinase inhibitors, the EtOAc extract of the fermentation broth of the strain Streptomyces sp. CA-129531 isolated from a Martinique sample, exhibited in cell free and cell-based assays the most promising activity (IC50 value of 63 µg/mL). Scaled-up production in a bioreactor led to the isolation of one new trichostatic acid analogue, namely trichostatic acid B (1), along with six known trichostatin derivatives (2-7), four diketopiperazines (8-11), two butyrolactones (12-13) and one hydroxamic acid siderophore (14). Among them, trichostatin A (4) showed a Ki value of 6.1 µM and six times stronger anti-tyrosinase activity (IC50 2.18 µΜ) than kojic acid (IC50 14.07 µΜ) used as a positive control. Deoxytrichostatin A (6) displayed also strong inhibitory activity against tyrosinase (IC50 19.18 µΜ). Trichostatin A production in bioreactor started together with the exponential phase of growth (day 4) and the maximum concentration was reached at day 9 (2.67 ± 0.13 µg/mL). Despite the cytotoxicity of some individual components, the EtOAc extract showed no cytotoxic effect on HepG2, A2058, A549, MCF-7 and MIA PaCa-2 cell lines, (IC50 >2.84 mg/mL) and against BG fibroblasts at the concentrations where the whitening effect was exerted, reassuring its safety and great tyrosinase inhibitory potential.

3.
SLAS Discov ; 25(3): 299-309, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31751168

RESUMO

Coenzyme Q10 (CoQ10) deficiency syndrome is a rare disease included in the family of mitochondrial diseases, which is a heterogeneous group of genetic disorders characterized by defective energy production. CoQ10 biosynthesis in humans requires at least 11 gene products acting in a multiprotein complex within mitochondria. The high-throughput screening (HTS) method based on the stabilization of the CoQ biosynthesis complex (Q-synthome) produced by the COQ8 gene overexpression is proven here to be a successful method for identifying new molecules from natural extracts that are able to bypass the CoQ6 deficiency in yeast mutant cells. The main features of the new approach are the combination of two yeast targets defective in genes with different functions on CoQ6 biosynthesis to secure the versatility of the molecule identified, the use of glycerol as a nonfermentable carbon source providing a wide growth window, and the stringent conditions required to mark an extract as positive. The application of this pilot approach to a representative subset of 1200 samples of the Library of Natural Products of Fundación MEDINA resulted in the finding of nine positive extracts. The fractionation of three of the nine extracts allowed the identification of five molecules; two of them are present in molecule databases of natural extracts and three are nondescribed molecules. The use of this screening method opens the possibility of discovering molecules with CoQ10-bypassing action useful as therapeutic agents to fight against mitochondrial diseases in human patients.

4.
Sci Rep ; 9(1): 20198, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882610

RESUMO

Colorectal cancer is one of the main causes of cancer death worldwide, and novel biomarkers are urgently needed for its early diagnosis and treatment. The utilization of metabolomics to identify and quantify metabolites in body fluids may allow the detection of changes in their concentrations that could serve as diagnostic markers for colorectal cancer and may also represent new therapeutic targets. Metabolomics generates a pathophysiological 'fingerprint' that is unique to each individual. The purpose of our study was to identify a differential metabolomic signature for metastatic colorectal cancer. Serum samples from 60 healthy controls and 65 patients with metastatic colorectal cancer were studied by liquid chromatography coupled to high-resolution mass spectrometry in an untargeted metabolomic approach. Multivariate analysis revealed a separation between patients with metastatic colorectal cancer and healthy controls, who significantly differed in serum concentrations of one endocannabinoid, two glycerophospholipids, and two sphingolipids. These findings demonstrate that metabolomics using liquid-chromatography coupled to high-resolution mass spectrometry offers a potent diagnostic tool for metastatic colorectal cancer.

5.
Curr Opin Microbiol ; 51: 81-87, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31739283

RESUMO

Microbial natural products have been one of the most important sources for the discovery of potential new antibiotics. However, the decline in the number of new chemical scaffolds discovered and the rediscovery problem of old known molecules has become a limitation for discovery programs developed by an industry confronted by a lack of incentives and a broken economic model. In contrast, the emergence of multidrug resistance in key pathogens has continued to progress and this issue is compounded by a lack of new antibiotics in development to address most of the difficult to treat infections. Advances in genome mining have confirmed the richness of biosynthetic gene clusters (BGCs) in the majority of microbial sources, and this suggests that an untapped chemical diversity is waiting to be discovered. The development of new genome engineering and synthetic biology tools, and the implementation of comparative omic approaches is fostering the development of new integrated culture-based strategies and genomic-driven approaches aimed at delivering new chemical classes of antibiotics.

6.
Metabolites ; 9(10)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546616

RESUMO

Fungi are one of the most prolific sources of microbial secondary metabolites. The production of new metabolites can be achieved using multiple fermentation conditions and by adding small-molecule effectors, including epigenetic modifiers. In the framework of our Natural Product screening programme targeting the discovery of new antimicrobial compounds, we applied multiple fermentation conditions and adsorptive polymeric resins on a large collection of fungal endophytes, to increase and stimulate their fungal secondary metabolite production. During this work the endophytic fungus Dimorphosporicola tragani CF-090383 showed antimicrobial activity only when grown in presence of adsorptive polymeric resins. In addition, seven epigenetic modifiers were added to fermentations of this endophytic fungus, in an attempt to activate its cryptic pathways as well as to analyse the metabolites produced under these conditions. D. tragani was seen to produce three different mycotoxin dendrodolides when the epigenetic modifiers 5-azacytidine and valproic acid were added to the fermentations, and these compounds were further characterized. However, the fungus produced the fatty acid synthesis inhibitor cerulenin, a molecule not previously described to be produced by this fungal species, only when cultivated in presence of the XAD-16 resin. We have found that the addition of XAD-16 resin resulted in four-fold higher titers in the production of cerulenin when compared to the best production conditions described in literature for the original fungal producer strain, Cephalosporium caerulens KF-140 (=Sarocladium oryzae), in a zeolite-based fermentation, used as an ammonium ion-trapping agent. The production of cerulenin by this strain of D. tragani, represents an alternative source for the improved production of cerulenin with better yields.

7.
J Biotechnol ; 301: 88-96, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31152756

RESUMO

From a large screening of microbial extracts for the discovery of proteasome modulating natural products, the fungal strain Cercospora sp. (CF-223709) was selected as the most promising for further investigation. Different liquid cultures of the strain were initially screened for their anti-oxidant activity (DPPH, ABTS) and for their cytotoxicity against the A2058, HepG2 and CCD25sk cell lines. A detailed chemical analysis and evaluation of the capacity to activate 26S-proteasome was followed for the most active extract. Three main polyketides were isolated and characterized by extensive analysis of NMR and HRMS spectra data as penialidine F (1), fulvic acid (2), and SB238569 (3). Fulvic acid showed the most significant anti-oxidant activity. Its IC50 value (8.16 µM) against the ABTS radical resulted 3-fold lower than the standard trolox. Fulvic acid also demonstrated a significant effect on proteasome by enhancing the chymotrypsin- and caspase-like activities of the 26S proteasome of human fibroblasts by 71.43% and 37.5% at 1 µM, respectively. Furthermore by scaling up the culture in a 30 L submerged bioreactor, Cercospora sp. produced up to 162.6 ±â€¯1.3 mg of fulvic acid/L. Our findings suggest that CF-223709 can be a promising source of proteasome activating natural compounds.


Assuntos
Ascomicetos/metabolismo , Produtos Biológicos , Reatores Biológicos/microbiologia , Policetídeos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Antioxidantes , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo
8.
Molecules ; 24(12)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208056

RESUMO

The strain Streptomyces osmaniensis CA-244599 isolated from the Comoros islands was submitted to liquid-state fermentation coupled to in situ solid-phase extraction with amberlite XAD-16 resin. Elution of the trapped compounds on the resin beads by ethyl acetate afforded seven metabolites, osmanicin (1), streptazolin (2), streptazone C (3), streptazone B1 (4), streptenol C (5), nocardamine (6) and desmethylenylnocardamine (7). Osmanicin (1) is a newly reported unusual scaffold combining streptazolin (2) and streptazone C (3) through a Diels-Alder type reaction. Experimental evidence excluded the spontaneous formation of 1 from 2 and 3. The isolated compounds were evaluated for their ability to inhibit elastase using normal human diploid fibroblasts. Compound 1 exhibited the most potent activity with an IC50 of 3.7 µM.


Assuntos
Alcaloides/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Elastase Pancreática/antagonistas & inibidores , Policetídeos/farmacologia , Streptomyces/química , Alcaloides/biossíntese , Alcaloides/química , Alcaloides/isolamento & purificação , Vias Biossintéticas , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fermentação , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Policetídeos/química , Policetídeos/isolamento & purificação , Policetídeos/metabolismo , RNA Ribossômico 16S/genética , Streptomyces/classificação , Streptomyces/genética
9.
Molecules ; 24(9)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086077

RESUMO

It is well known that terrestrial environments host an immense microbial biodiversity. Exposed to different types of stress, such as UV radiation, temperature fluctuations, water availability and the inter- / intra-specific competition for resources, terrestrial microorganisms have been evolved to produce a large spectrum of bioactive molecules. Bacteria, archaea, protists, fungi and algae have shown a high potential of producing biomolecules for pharmaceutical or other industrial purposes as they combine a sustainable, relatively low-cost and fast-production process. Herein, we provide an overview of the different bioactive molecules produced by terrestrial microorganisms with skin protecting applications. The high content in polyphenolic and carotenoid compounds produced by several strains, as well as the presence of exopolysaccharides, melanins, indole and pyrrole derivatives, mycosporines, carboxylic acids and other molecules, are discussed in the context of their antioxidant, photo-protective and skin-whitening activity. Relevant biotechnological tools developed for the enhanced production of high added value natural products, as well as the protecting effect of some antioxidant, hydrolytic and degrading enzymes are also discussed. Furthermore, we describe classes of microbial compounds that are used or have the potential to be used as antimicrobials, moisturizers, biosurfactants, pigments, flavorings and fragrances.


Assuntos
Produtos Biológicos/análise , Biotecnologia/métodos , Cosméticos/análise , Antioxidantes/análise , Archaea/metabolismo , Bactérias/metabolismo , Cosméticos/metabolismo , Fungos/metabolismo
10.
ACS Infect Dis ; 5(8): 1317-1326, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31099236

RESUMO

MTBVAC is a live attenuated M. tuberculosis vaccine constructed by genetic deletions in the phoP and fadD26 virulence genes. The MTBVAC vaccine is currently in phase 2 clinical trials with newborns and adults in South Africa, one of the countries with the highest incidence. Although MTBVAC has been extensively characterized by genomics, transcriptomics, lipidomics, and proteomics, its metabolomic profile is yet unknown. Accordingly, in this study we aim to identify differential metabolites between M. tuberculosis and MTBVAC. To this end, an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry was implemented in order to explore the main metabolic differences between M. tuberculosis and MTBVAC. As an outcome, we identified a set of 34 metabolites involved in diverse bacterial biosynthetic pathways. A consistent increase in the phosphatidylinositol species was observed in the vaccine candidate relative to its parental strain. This phenotype resulted in an increased production of phosphatidylinositol mannosides, a novel PhoP-regulated phenotype in the most widespread lineages of M. tuberculosis. This study represents a step ahead in our understanding of the MTBVAC vaccine, and some of the differential metabolites identified in this work might be used as potential vaccination biomarkers.

11.
Mol Pharm ; 16(4): 1456-1466, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30821469

RESUMO

The macrolide caniferolide A was isolated from extracts of a culture of the marine-derived actinomycete Streptomyces caniferus, and its ability to ameliorate Alzheimer's disease (AD) hallmarks was determined. The compound reduced neuroinflammatory markers in BV2 microglial cells activated with lipopolysaccharide (LPS), being able to block NFκB-p65 translocation to the nucleus and to activate the Nrf2 pathway. It also produced a decrease in pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), reactive oxygen species (ROS) and nitric oxide release and inhibited iNOS, JNK, and p38 activities. Moreover, the compound blocked BACE1 activity and attenuated Aß-activation of microglia by drastically diminishing ROS levels. The phosphorylated state of the tau protein was evaluated in SH-SY5Y tau441 cells. Caniferolide A reduced Thr212 and Ser214 phosphorylation by targeting p38 and JNK MAPK kinases. On the other side, the antioxidant properties of the macrolide were determined in an oxidative stress model with SH-SY5Y cells treated with H2O2. The compound diminished ROS levels and increased cell viability and GSH content by activating the nuclear factor Nrf2. Finally, the neuroprotective ability of the compound was confirmed in two trans-well coculture systems with activated BV2 cells (both with LPS and Aß) and wild type and transfected SH-SY5Y cells. The addition of caniferolide A to microglial cells produced a significant increase in the survival of neuroblastoma in both cases. These results indicate that the compound is able to target many pathological markers of AD, suggesting that caniferolide A could be an interesting drug lead for a polypharmacological approach to the illness.

12.
Org Biomol Chem ; 17(11): 2954-2971, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30806648

RESUMO

Bioassay-guided isolation based on the antifungal activity of a culture broth of the marine-derived actinomycete Streptomyces caniferus CA-271066 led to the discovery of new 36-membered polyol macrolides, caniferolides A-D (1-4). Their connectivity was determined by spectroscopic methods including ESITOF-MS and 1D/2D NMR. The relative stereochemistry of each stereocluster in these compounds was established using NOE analysis, the universal database method and J-based configuration analysis, further assisted by comparisons with NMR data of structurally related macrolides. Genome sequencing followed by detailed bioinformatics analysis led to the identification of the corresponding biosynthetic gene cluster and allowed the prediction of the stereochemical outcome of their biosynthesis, confirming the relative stereochemistry of each stereocluster already determined by NMR and establishing their stereochemical relationship, ultimately rendering the absolute configuration of all chiral centers. Furthermore, based on our results and already published data, it has been possible to derive the complete absolute configuration of the related macrolides PM100117 and PM100118, astolides A and B, and deplelides A and B. Caniferolides A-D have shown pronounced antifungal activity against Candida albicans and Aspergillus fumigatus alongside antiproliferative activity against five human tumoral cell lines.


Assuntos
Vias Biossintéticas/genética , Macrolídeos/química , Família Multigênica , Streptomyces/química , Streptomyces/genética , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macrolídeos/isolamento & purificação , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Polímeros/química , Polímeros/isolamento & purificação , Polímeros/farmacologia , Estereoisomerismo , Streptomyces/metabolismo
13.
SLAS Discov ; 24(3): 398-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616481

RESUMO

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.

14.
Nat Prod Res ; 33(1): 66-73, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29411643

RESUMO

A new medermycin derivative, MDN-0171 (1), and two known structurally related compounds, medermycin (2) and antibiotic G15-F (3) were isolated from the acetone extract of culture broths of the marine-derived Streptomyces albolongus strain CA-186053. Their structures were determined using a combination of spectroscopic techniques, including 1D and 2D NMR and electrospray-time of flight mass spectrometry (ESI-TOF MS). Compounds 2 and 3 accounted for the antimicrobial activity (against methicillin-resistant Staphylococcus aureus and Escherichia coli) previously detected in the crude extract of this actinomycete.


Assuntos
Streptomyces/química , Actinobacteria , Antibacterianos/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Naftoquinonas/química , Análise Espectral
15.
Mar Drugs ; 18(1)2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31888028

RESUMO

As part of our continuing efforts to discover new bioactive compounds from microbial sources, a reinvestigation of extracts of scaled-up cultures of the marine-derived Streptomyces sp. strain CA-271078 resulted in the isolation and structural elucidation of four new napyradiomycins (1-3, 5). The known napyradiomycin SC (4), whose structural details had not been previously described in detail, and another ten related known compounds (6-15). The structures of the new napyradiomycins were characterized by HRMS and 1D- and 2D-NMR spectroscopies and their relative configurations were established through a combination of molecular modelling with nOe and coupling constants NMR analysis. The absolute configuration of each compound is also proposed based on biosynthetic arguments and the comparison of specific rotation data with those of related compounds. Among the new compounds, 1 was determined to be the first non-halogenated member of napyradiomycin A series containing a functionalized prenyl side chain, while 2-4 harbor in their structures the characteristic chloro-cyclohexane ring of the napyradiomycin B series. Remarkably, compound 5 displays an unprecedented 14-membered cyclic ether ring between the prenyl side chain and the chromophore, thus representing the first member of a new class of napyradiomycins that we have designated as napyradiomycin D1. Anti-infective and cytotoxic properties for all isolated compounds were evaluated against a set of pathogenic microorganisms and the HepG2 cell line, respectively. Among the new compounds, napyradiomycin D1 exhibited significant growth-inhibitory activity against methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, and HepG2.

16.
Front Microbiol ; 9: 2791, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524403

RESUMO

The xenobiotic response element (XRE) transcription factors belong to a regulator family frequently found in Streptomyces that are often followed by small proteins with a DUF397 domain. In fact, the pair XRE-DUF397 has been proposed to comprise toxin-antitoxin (TA) type II systems. In this work, we demonstrate that one of these putative TA-systems, encoded by the genes SCO4441 and SCO4442 of Streptomyces coelicolor, and denominated Scr1/Scr2 (which stands for S. c oelicolor r egulator), does not behave as a toxin-antitoxin system under the conditions used as was originally expected. Instead the pair Scr1/Scr2 acts as a strong positive regulator of endogenous antibiotic production in S. coelicolor. The analysis of the 19 Streptomyces strains tested determined that overexpression of the pair Scr1/Scr2 drastically induces the production of antibiotics not only in S. coelicolor, but also in Streptomyces lividans, Streptomyces peucetius, Streptomyces steffisburgensis and Streptomyces sp. CA-240608. Our work also shows that Scr1 needs Scr2 to exert positive regulation on antibiotic production.

17.
BMC Syst Biol ; 12(Suppl 5): 99, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458793

RESUMO

BACKGROUND: Spatial localization of natural products or proteins during microbial interactions can help to identify new antimicrobials both as offensive or defensive agents. Visible spatial interactions have been used for decades to enhance Drug Discovery processes both in industry and academia. RESULTS: Herein we describe an automated micro-extraction methodology, that coupled with the previously described HPLC-Studio 2.0 software and the new development, the MASS-Studio 1.0 software, can combine multiple chemical analyses to generate ultraviolet (UV) and mass spectrometry (MS) images from traditional affordable analytical equipment. As a proof of concept, we applied this methodology on two microbial antagonisms observed among co-habitant endophytes isolated from endemic plants of arid areas of the south of Europe. CONCLUSIONS: The use of UV and MS images highlighted interacting naturals products and allowed clear identification of induced molecules of interest not produced by the strains when cultured individually.


Assuntos
Anti-Infecciosos/química , Descoberta de Drogas/métodos , Interações Microbianas , Anti-Infecciosos/metabolismo , Bactérias/crescimento & desenvolvimento , Técnicas de Cocultura , Espectrometria de Massas , Estudo de Prova de Conceito , Raios Ultravioleta
18.
Antibiotics (Basel) ; 7(4)2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257490

RESUMO

The current spread of multi-drug resistance in a number of key pathogens and the lack of therapeutic solutions in development to address most of the emerging infections in the clinic that are difficult to treat have become major concerns. Microbial natural products represent one of the most important sources for the discovery of potential new antibiotics and actinomycetes have been one of the most relevant groups that are prolific producers of these bioactive compounds. Advances in genome sequencing and bioinformatic tools have collected a wealth of knowledge on the biosynthesis of these molecules. This has revealed the broad untapped biosynthetic diversity of actinomycetes, with large genomes and the capacity to produce more molecules than previously estimated, opening new opportunities to identify the novel classes of compounds that are awaiting to be discovered. Comparative genomics, metabolomics and proteomics and the development of new analysis and genetic engineering tools provide access to the integration of new knowledge and better understanding of the physiology of actinomycetes and their tight regulation of the production of natural products antibiotics. This new paradigm is fostering the development of new genomic-driven and culture-based strategies, which aims to deliver new chemical classes of antibiotics to be developed to the clinic and replenish the exhausted pipeline of drugs for fighting the progression of infection diseases in the near future.

19.
Neuropharmacology ; 141: 283-295, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30205103

RESUMO

Alzheimer's disease (AD) is a pathology characterized by the abnormal accumulation of amyloid-beta (Aß) and hyperphosphorylated tau. Oxidative stress and neuroinflammation are also strongly related to this disease. The ability of two new glycosylated angucyclinones, streptocyclinones A and B (1 and 2), isolated from Streptomyces sp to improve AD hallmarks was evaluated. Compounds were able to protect SH-SY5Y neuroblastoma cells from H2O2-induced oxidative injury by activating the nuclear factor E2-related factor (Nrf2). Their capacity to modulate neuroinflammation was tested in lipopolysaccharide-activated BV2 microglial cells. Compounds reduced the release of pro-inflammatory factors, inhibited the activation of NFκB and mitogen activated kinases (MAPK), and induced the translocation of Nrf2 to the nucleus of microglial cells. A trans-well co-culture was established to determine the effect of microglia treated with streptocyclinones on the survival of SH-SY5Y cells. The cell viability of neuroblastoma cells increased when the compounds were added to BV2 cells. SH-SY5Y-TMHT441 cells were used to determine the effect of compounds on tau phosphorylation. Both compounds reduced tau hyperphophorylation by targeting MAPK kinases. Moreover, streptocyclinone B (2) was able to inhibit the activity of ß-secretase 1 and decrease the release of reactive oxygen species in BV2 cells stimulated with Aß. With the same co-culture trans-well system, the treatment of Aß-stimulated microglia with compound 2 augmented the viability of SH-SY5Y-TMHT441 cells. The results presented in this work provide evidences of the multitarget activities displayed by these new Streptomyces compounds, making them good candidates for further studies in the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Antraquinonas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Antraquinonas/química , Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Humanos , Peróxido de Hidrogênio , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas tau/metabolismo
20.
J Nat Prod ; 81(7): 1687-1691, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-29924612

RESUMO

A potent antiplasmodial polycyclic xanthone, MDN-0185 (1), was isolated from an unidentified species of the genus Micromonospora. The planar structure of 1 was established as a seven-ring polycyclic xanthone with partial structures very similar to two known natural products, namely, xantholipin and Sch 54445. Using ROESY correlations, the relative stereochemistry of the two independent stereoclusters of compound 1 could be determined. Mosher analysis and comparison of the specific rotation of compound 1 with that of xantholipin allowed the determination of its absolute configuration. Compound 1 exhibited an IC50 of 9 nM against Plasmodium falciparum 3D7 parasites.


Assuntos
Antimaláricos/isolamento & purificação , Micromonospora/química , Plasmodium falciparum/efeitos dos fármacos , Compostos Policíclicos/isolamento & purificação , Xantonas/isolamento & purificação , Antimaláricos/química , Antimaláricos/farmacologia , Estrutura Molecular , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Xantonas/química , Xantonas/farmacologia
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