Screening for tyrosinase inhibitors from actinomycetes; identification of trichostatin derivatives from Streptomyces sp. CA-129531 and scale up production in bioreactor

  • Bioorg Med Chem Lett. 2020 Mar 15;30(6):126952. doi: 10.1016/j.bmcl.2020.126952.
Katerina Georgousaki  1 ,  Nikolaos Tsafantakis  1 ,  Sentiljana Gumeni  2 ,  Ignacio Gonzalez  3 ,  Thomas Andrew Mackenzie  3 ,  Fernando Reyes  3 ,  Carole Lambert  4 ,  Ioannis P Trougakos  2 ,  Olga Genilloud  3 ,  Nikolas Fokialakis  5
Affiliations
  • 1. Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
  • 2. Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
  • 3. Fundacion MEDINA, Health Sciences Technology Park, Granada, Spain.
  • 4. Givaudan France SAS, Active Beauty, Pomacle, France.
  • 5. Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: [email protected].
PMID: 32005414 DOI: 10.1016/j.bmcl.2020.126952
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.

Keywords
Bioreactor; Enzyme kinetics studies; Secondary metabolites, Streptomyces sp.; Trichostatin derivatives; Tyrosinase inhibitors.