Search for histone deacetylase inhibitors from marine Actinomycetales

The marine environment is recognized as the space with the highest biodiversity on earth and is hence, an abundant source for new lead structures and drugs [1]. Due to their symbiotic associations with other organisms, microbes are supposed to produce the highest number and variety of marine secondary metabolites [2]. Among microorganisms, bacteria of the order Actinomycetales are most promising for finding new structures because 45% of all previously discovered microbial secondary metabolites derive from this order [1]. These facts prompted us to focus our search for inhibitors of histone deacetylases (HDACs) on marine Actinomycetales. The enzyme complex of HDACs plays a significant role in the super- and uncoiling of DNA and it has been proven that it has an increased activity in tumor tissues. Consequently, HDAC inhibitors attracted attention as a new group of anti-cancer drugs [3]. In our project, 8 strains of marine Actinomycetales were cultured and 5 extracts from each strain were produced: a dichloromethane, an ethyl acetate, a methanolic and an aqueous extract of the mycelium, as well as an acetone extract from the resin XAD-16 which was applied to adsorb released metabolites from the culture medium. For the determination of the inhibitory activity of the extracts on HDAC, they were screened in an HDAC-assay which in-house has been optimized for activity-guided screening [4]. The acetone extracts of the strains Williamsia maris and Actinoalloteichus hymeniacidonis showed an inhibition of 65.3 ± 0.59% and 67.6 ± 2.58% respectively at a concentration of 1.67 mg/ml. In summary, the first steps of our work point to the presence of HDAC inhibiting secondary metabolites in two out of 30 extracts.

References:

[1] Subramani R, Aalbersberg W. Marine actinomycetes: an ongoing source of novel bioactive metabolites. Microbiol Res. 2012; 167(10): 571 – 580.

[2] Gerwick WH, Fenner AM. Drug discovery from marine microbes. Microb Ecol. 2013; 65(4): 800 – 806.

[3] de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003; 370(Pt 3): 737 – 749.

[4] Krasteva S, Heiss E, Krenn L. Optimization and application of a fluorimetric assay for the identification of histone deacetylase inhibitors from plant origin. Pharm Biol. 2011; 49(6): 658 – 668.