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Cercospora sp. as a source of anti-aging polyketides targeting 26S proteasome and scale-up production in submerged bioreactor

Georgousaki, Katerina, Tsafantakis, Nikolaos, Gumeni, Sentiljana, González-Menéndez, Victor, de Pedro, Nuria, Tormo, José Rubén, Almeida, Celso, Lambert, Carole, Genilloud, Olga, Trougakos, Ioannis P., Fokialakis, Nikolas
Journal of biotechnology 2019 v.301 pp. 88-96
2,2-diphenyl-1-picrylhydrazyl, Cercospora, antioxidant activity, bioreactors, cell lines, chemical analysis, cytotoxicity, fibroblasts, fulvic acids, fungi, humans, inhibitory concentration 50, liquids, mass spectrometry, nuclear magnetic resonance spectroscopy, polyketides, proteasome endopeptidase complex, screening
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 ± 1.3 mg of fulvic acid/L. Our findings suggest that CF-223709 can be a promising source of proteasome activating natural compounds.