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1.
Sci Rep ; 12(1): 1649, 2022 01 31.
Article in English | MEDLINE | ID: mdl-35102193

ABSTRACT

As part of our screening program for the discovery of molecules of microbial origin with skin-whitening activity, 142 diverse fungal endophytes from a wide variety of Andalusia arid plants were screened, applying the OSMAC approach. The fungal strains CF-090361 and CF-090766, isolated from xerophytic plants, were selected as the most promising, while phylogenetic analysis revealed that both strains could represent a new species within the genus Comoclathris. The effect of different fermentation conditions on the production of tyrosinase inhibitory activity was examined, in order to identify the optimum cultivation conditions. LCMS based metabolomics was applied to determine significant differences between the strains and fermentation conditions, and to identify potential bioactive secondary metabolites. Bioassay-guided purification of the main active components led to the isolation of three new compounds (1-3), along with the known compounds graphostrin B (4) and brevianamide M (5). Compound 1 (Comoclathrin) demonstrated the strongest anti-tyrosinase activity (IC50 0.16 µΜ), which was 90-times higher than kojic acid (IC50 14.07 µΜ) used as positive control. Additionally, comoclathrin showed no significant cytotoxicity against a panel of cancer cell lines (HepG2, A2058, A549, MCF-7 and MIA PaCa-2) and normal BJ fibroblasts. These properties render comoclathrin an excellent development candidate as whitening agent.


Subject(s)
Ascomycota/metabolism , Endophytes/metabolism , Enzyme Inhibitors/pharmacology , Monophenol Monooxygenase/antagonists & inhibitors , Plants/microbiology , Skin Lightening Preparations/pharmacology , A549 Cells , Ascomycota/genetics , Cell Survival/drug effects , Desert Climate , Endophytes/genetics , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/toxicity , Hep G2 Cells , Humans , MCF-7 Cells , Metabolome , Metabolomics , Monophenol Monooxygenase/metabolism , Phylogeny , Skin Lightening Preparations/isolation & purification , Skin Lightening Preparations/toxicity
2.
Nat Prod Res ; 36(6): 1668-1671, 2022 Mar.
Article in English | MEDLINE | ID: mdl-33706628

ABSTRACT

Three known compounds were isolated from Virgaria nigra CF-231658; 2,7-dihydroxy naphthalene (1), virgaricin B (2) and virgaricin (3). The isolated compounds was obtained from liquid-state and agar-supported fermentation using Amberlite XAD-16 solid-phase extraction during the cultivation step. Their structures were elucidated on the basis of 1D and 2D NMR as well as HRMS spectroscopic analyses. The isolated compounds were examined for their ability to inhibit elastase using normal human diploid fibroblasts. Compound 2 displayed the most potent activity with 76.7 ± 2.12% inhibition of the enzyme activity at 5 µM concentration.


Subject(s)
Ascomycota , Ascomycota/chemistry , Fermentation , Humans , Lactams/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Pancreatic Elastase/antagonists & inhibitors
3.
Molecules ; 25(3)2020 Feb 04.
Article in English | MEDLINE | ID: mdl-32033190

ABSTRACT

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.


Subject(s)
Autophagy/physiology , Coriolaceae/chemistry , Hydroxybenzoates/pharmacology , Lysosomes/physiology , Proteostasis/drug effects , Benzoic Acid/pharmacology , Cathepsins/metabolism , Cell Extracts/pharmacology , Cell Line , Coriolaceae/metabolism , Humans , Hydroxybenzoates/chemistry , Molecular Docking Simulation , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Ubiquitin-Protein Ligases/metabolism
4.
Bioorg Med Chem Lett ; 30(6): 126952, 2020 03 15.
Article in English | MEDLINE | ID: mdl-32005414

ABSTRACT

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.


Subject(s)
Actinobacteria/chemistry , Complex Mixtures/chemistry , Enzyme Inhibitors/chemistry , Hydroxamic Acids/chemistry , Monophenol Monooxygenase/antagonists & inhibitors , Streptomyces/chemistry , Bioreactors , Cell Survival/drug effects , Complex Mixtures/metabolism , Diketopiperazines/chemistry , Enzyme Activation/drug effects , Enzyme Inhibitors/metabolism , Fermentation , Fibroblasts/cytology , Fibroblasts/drug effects , Humans , Hydroxamic Acids/metabolism , Lactones/chemistry , Mass Screening , Pyrones/chemistry , Secondary Metabolism/drug effects
5.
Molecules ; 24(12)2019 Jun 15.
Article in English | MEDLINE | ID: mdl-31208056

ABSTRACT

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.


Subject(s)
Alkaloids/pharmacology , Fibroblasts/drug effects , Fibroblasts/metabolism , Pancreatic Elastase/antagonists & inhibitors , Polyketides/pharmacology , Streptomyces/chemistry , Alkaloids/biosynthesis , Alkaloids/chemistry , Alkaloids/isolation & purification , Biosynthetic Pathways , Cell Survival/drug effects , Dose-Response Relationship, Drug , Fermentation , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Molecular Structure , Polyketides/chemistry , Polyketides/isolation & purification , Polyketides/metabolism , RNA, Ribosomal, 16S/genetics , Streptomyces/classification , Streptomyces/genetics
6.
J Biotechnol ; 301: 88-96, 2019 Aug 10.
Article in English | MEDLINE | ID: mdl-31152756

ABSTRACT

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.


Subject(s)
Ascomycota/metabolism , Biological Products , Bioreactors/microbiology , Polyketides , Proteasome Endopeptidase Complex/drug effects , Antioxidants , Cell Line , Cell Survival/drug effects , Humans , Proteasome Endopeptidase Complex/metabolism
7.
Molecules ; 24(9)2019 May 13.
Article in English | MEDLINE | ID: mdl-31086077

ABSTRACT

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.


Subject(s)
Biological Products/analysis , Biotechnology/methods , Cosmetics/analysis , Antioxidants/analysis , Archaea/metabolism , Bacteria/metabolism , Cosmetics/metabolism , Fungi/metabolism
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