Epigenetic Tailoring for the Production of Anti-Infective Cytosporones from the Marine Fungus Leucostoma persoonii

Marine Drugs

Jeremy Beau²  Nida Mahid²  Whittney N. Burda³  Lacey Harrington³  Lindsey N. Shaw³  Tina Mutka¹  Dennis E. Kyle¹  Betty Barisic¹  Alberto van Olphen¹ 

[1] Department of Global Health, University of South Florida, Tampa, FL 33620, USA;Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, University of South Florida, Tampa, FL 33620, USA;Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA;

关键词: epigenetics;    fungus;    mangrove;    MRSA;    malaria;   

DOI  :  10.3390/md10040762

来源: mdpi

【 摘 要 】

Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones. Epigenetic modifiers employed to activate secondary metabolite genes resulted in enhanced production of known cytosporones B (1, 360%), C (2, 580%) and E (3, 890%), as well as the production of the previously undescribed cytosporone R (4). Cytosporone E was the most bioactive, displaying an IC₉₀ of 13 µM toward Plasmodium falciparum, with A549 cytotoxicity IC₉₀ of 437 µM, representing a 90% inhibition therapeutic index (TI₉₀ = IC₉₀ A459/IC₉₀ P. falciparum) of 33. In addition, cytosporone E was active against MRSA with a minimal inhibitory concentration (MIC) of 72 µM and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 µM).

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.