期刊
MARINE DRUGS
卷 10, 期 4, 页码 762-774出版社
MDPI
DOI: 10.3390/md10040762
关键词
epigenetics; fungus; mangrove; MRSA; malaria
资金
- Medicines for Malaria Ventures [MMV08/0105]
- National Institute of Allergies and Infectious Diseases [1R01AI080626-01A2]
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 mu M toward Plasmodium falciparum, with A549 cytotoxicity IC90 of 437 mu M, 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 mu M and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 mu M).
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